546 results on '"AMYLOID plaque"'
Search Results
2. Digital whole‐slide imaging of changes in amyloid after peripheral blood stem cell transplantation in patients with amyloid light‐chain amyloidosis.
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Kono, Kei, Sawa, Naoki, Wake, Atsushi, Shintani‐Domoto, Yukako, Fujii, Takeshi, Takazawa, Yutaka, Ubara, Yoshifumi, and Ohashi, Kenichi
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STEM cell transplantation , *AMYLOID plaque , *AMYLOID , *BLOOD cells , *BLOOD vessels , *CARDIAC amyloidosis - Abstract
Peripheral blood stem cell transplantation (PBSCT) has made amyloid light‐chain (AL) amyloidosis treatable. After PBSCT, hematological complete remission (HCR) can be achieved, leading to improved renal prognosis. The purpose of this study was to evaluate whether whole slide imaging of biopsy samples shows a post‐treatment reduction in amyloid deposits in patients with AL amyloidosis. Patients were divided into three groups: Group A (n = 8), not eligible for PBSCT and treated with other therapies; Group B (n = 11), treated with PBSCT and achieved HCR; and Group C (n = 5), treated with PBSCT but did not achieve HCR. Clinical findings and amyloid deposition in glomeruli, interstitium, and blood vessels were compared before and after treatment using digital whole‐slide imaging. Proteinuria and hypoalbuminemia improved more in Group B than in the other groups, and in Group B, amyloid deposition improved more in the glomeruli than in the interstitium and blood vessels. The long‐term renal and survival prognosis was better in Group B than in the other groups. PBSCT can be expected to improve long‐term clinical and renal histological prognosis in patients with AL amyloidosis who achieve HCR. Amyloid disappearance from renal tissue may take a long time even after clinical HCR. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Development of a New Positron Emission Tomography Imaging Radioligand Targeting RIPK1 in the Brain and Characterization in Alzheimer's Disease.
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Bai, Ping, Lan, Yu, Liu, Yan, Mondal, Prasenjit, Gomm, Ashley, Xu, Yulong, Wang, Yanli, Wang, Yongle, Kang, Leyi, Pan, Lili, Bagdasarian, Frederick A., Hallisey, Madelyn, Lobo, Fleur, Varela, Breanna, Choi, Se Hoon, Gomperts, Stephen N., Wey, Hsiao‐Ying, Shen, Shiqian, Tanzi, Rudolph E., and Wang, Changning
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POSITRON emission tomography , *ALZHEIMER'S disease , *RECEPTOR-interacting proteins , *AMYLOID plaque , *PROTEIN kinases - Abstract
Targeting receptor‐interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic stratagem for neurodegenerative disorders, particularly Alzheimer's disease (AD). A positron emission tomography (PET) probe enabling brain RIPK1 imaging can provide a powerful tool to unveil the neuropathology associated with RIPK1. Herein, the development of a new PET radioligand, [11C]CNY‐10 is reported, which may enable brain RIPK1 imaging. [11C]CNY‐10 is radiosynthesized with a high radiochemical yield (41.8%) and molar activity (305 GBq/µmol). [11C]CNY‐10 is characterized by PET imaging in rodents and a non‐human primate, demonstrating good brain penetration, binding specificity, and a suitable clearance kinetic profile. It is performed autoradiography of [11C]CNY‐10 in human AD and healthy control postmortem brain tissues, which shows strong radiosignal in AD brains higher than healthy controls. Subsequently, it is conducted further characterization of RIPK1 in AD using [11C]CNY‐10‐based PET studies in combination with immunohistochemistry leveraging the 5xFAD mouse model. It is found that AD mice revealed RIPK1 brain signal significantly higher than WT control mice and that RIPK1 is closely related to amyloid plaques in the brain. The studies enable further translational studies of [11C]CNY‐10 for AD and potentially other RIPK1‐related human studies. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Non‐transgenic guinea pig strains exhibit divergent age‐related changes in hippocampal mitochondrial respiration.
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Walsh, Maureen A., Latham, Amanda S., Zhang, Qian, Jacobs, Robert A., Musci, Robert V., LaRocca, Thomas J., Moreno, Julie A., Santangelo, Kelly S., and Hamilton, Karyn L.
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GUINEA pigs , *RESPIRATION , *MITOCHONDRIA , *CELLULAR aging , *PRESBYCUSIS , *THETA rhythm , *ALZHEIMER'S disease , *MITOCHONDRIAL pathology , *AMYLOID plaque - Abstract
Aim: Alzheimer's disease (AD) is the most common form of dementia. However, while 150+ animal models of AD exist, drug translation from preclinical models to humans for treatment usually fails. One factor contributing to low translation is likely the absence of neurodegenerative models that also encompass the multi‐morbidities of human aging. We previously demonstrated that, in comparison to the PigmEnTed (PET) guinea pig strain which models "typical" brain aging, the Hartley strain develops hallmarks of AD like aging humans. Hartleys also exhibit age‐related impairments in cartilage and skeletal muscle. Impaired mitochondrial respiration is one driver of both cellular aging and AD. In humans with cognitive decline, diminished skeletal muscle and brain respiratory control occurs in parallel. We previously reported age‐related declines in skeletal muscle mitochondrial respiration in Hartleys. It is unknown if there is concomitant mitochondrial dysfunction in the brain. Methods: Therefore, we assessed hippocampal mitochondrial respiration in 5‐ and 12‐month Hartley and PET guinea pigs using high‐resolution respirometry. Results: At 12 months, PETs had higher complex I supported mitochondrial respiration paralleling their increase in body mass compared to 5 months PETs. Hartleys were also heavier at 12 months compared to 5 months but did not have higher complex I respiration. Compared to 5 months Hartleys, 12 months Hartleys had lower complex I mitochondrial efficiency and compensatory increases in mitochondrial proteins collectively suggesting mitochondrial dysfunction with age. Conclusions: Therefore, Hartleys might be a relevant model to test promising therapies targeting mitochondria to slow brain aging and AD progression. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Cysts of the ligamentum flavum are often linked to ischemic conditions: A morphological study.
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Matsunaga, Ayano, Saito, Mariko, Ijiri, Kaya, Tsuchiya, Motohiro, Yasuda, Akimasa, Kitamura, Kazuya, Ogata, Sho, Chiba, Kazuhiro, and Matsukuma, Susumu
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AMYLOID plaque , *HEMOSIDEROSIS , *CYSTS (Pathology) , *METAPLASIA , *OSSIFICATION - Abstract
"Cysts of the ligamentum flavum (cysts‐LF)" is the term for non‐neoplastic cystic lesion involving LF. The aim of the present study was to elucidate the histopathological characteristics and pathogenesis of "cysts‐LF". Herein, we defined cysts‐LF as spinal cysts containing degenerative LF components. From archival cases, we investigated 18 symptomatic cysts‐LF surgically removed from 18 patients (13 males and five females; median age 68.5 years [range, 42–86 years]). The elastic fibers of LF components in the wall were separated and/or torn, and cyst walls were accompanied by chondroid metaplasia (17 cases), myxoid changes (13 cases), ossification (11 cases), amyloid deposits (14 cases), hemosiderosis (six cases), granular/smudgy calcification (four cases), synovial cell linings (three cases), and severe inflammatory infiltrates (one case). These histologic features of our cysts‐LF were shared by previously reported "cysts‐LF." Fourteen cysts‐LF demonstrated vascular stenosis/occlusion, and eight showed thick hyalinized vessels, suggesting local circulatory insufficiency. Eight cases (44%) exhibited lipomembranous fat necrosis, accompanied by hyalinized vascular changes (p = 0.003). Ischemic conditions were observed in nearly half of the present cysts‐LF, and may be one of the main contributing factors for the formation of cysts‐LF, via degeneration and cystic changes in the LF. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Skeletal muscle involvement in systemic amyloidosis is often overlooked.
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Xu, Jingwen, Zhou, Xiaoyu, Wang, Yingxin, Liu, Wenzhu, Shan, Yi, Zhang, Dong, Lv, Huixia, Zhao, Dandan, Dai, Tingjun, Zhao, Yuying, Li, Wei, Liu, Fuchen, and Yan, Chuanzhu
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NERVE conduction studies , *AMYLOID plaque , *MUSCULAR atrophy , *MUSCLE strength , *IMMUNOHISTOCHEMISTRY - Abstract
Aim: Systemic amyloidosis is a condition in which misfolded amyloid fibrils are deposited within tissues. Amyloid myopathy is a rare manifestation of systemic amyloidosis. However, whether skeletal muscle involvement is underestimated and whether such deposition guarantees clinical and pathological myopathic features remain to be investigated. Methods: We retrospectively reviewed patients with systemic amyloidosis, in whom skeletal muscle biopsies were performed at our centre between January 2018 and June 2023. In total, 28 patients with suspected systemic amyloidosis were included. Among these, 21 presented with cardiomyopathy but lacked myopathic symptoms. The clinical and pathological data of these patients were further analysed. The amyloid type was confirmed by immunohistochemistry. Results: Twenty‐eight patients with suspected systemic amyloidosis underwent muscle biopsy. Amyloid deposition in the skeletal muscle was confirmed in 24 patients, including 22 with light‐chain amyloidosis (AL) and two with transthyretin amyloidosis (ATTR). Among the 24 patients, seven presented with muscle weakness and decreased muscle strength (Group 1, symptomatic myopathy), whereas the remaining 17 exhibited normal muscle strength (Group 2, asymptomatic myopathy). Group 1 included four patients with AL‐λ, one with AL‐κ and two with ATTR. Group 2 included 15 patients with AL‐λ and two patients with AL‐κ. In Group 1, six patients exhibited neuropathy, whereas only one patient in Group 2 presented with subclinical neuropathy on nerve conduction studies. Amyloid deposition in the interstitium was the most obvious change, observed in all 24 patients. Neuropathic changes, including denervation atrophy and muscle fibre grouping, were also common. Except for type 2 fibre atrophy, the other myopathic changes were mild and nonspecific. No sarcolemmal disruption was observed. Immunohistochemical analysis revealed marked positivity for MAC and MHC1 expression in the regions with amyloid deposits. Clinicopathological analysis revealed no significant differences in the extent of muscular amyloid deposition between the two groups. Nevertheless, patients in Group 1 displayed more pronounced neurogenic atrophy on skeletal muscle biopsies. Conclusions: Our study indicates that amyloid deposition in skeletal muscle is commonly observed but rarely causes symptomatic myopathy in systemic amyloidosis. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Targeting the hydrophobic region of pyroglutamate‐modified amyloid‐β by tyrocidine A prevents its nucleation–aggregation process and its "catalytic effect" on the Aβs aggregation.
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Qin, Wenjing, Chen, Daoyuan, Wang, Youqiao, Liu, Ziyi, Zhou, Binhua, Bu, Xianzhang, and Wen, Gesi
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ALZHEIMER'S disease ,CATALYSIS ,AMYLOID plaque ,PEPTIDES ,MOLECULES - Abstract
Pyroglutamate (pE)‐modified amyloid‐β (Aβ) peptides play a crucial role in the development of Alzheimer's disease. pEAβ3‐42 can rapidly form oligomers that gradually elongate hydrophobic segments to form β‐sheet‐rich amyloid intermediates, ultimately resulting in the formation of mature amyloid fibrils. pEAβ3‐42 can also catalyze the aggregation of Aβ species and subsequently accelerate the formation of amyloid senile plaques. Considering the recent clinical success of the pEAβ3‐42‐targeting antibody donanemab, molecules that strongly bind pEAβ3‐42 and prevent its aggregation and catalytic effect on Aβs may also provide potential therapeutic options for Alzheimer's disease. Here, we demonstrate that the natural antibiotic cyclopeptide tyrocidine A (TA) not only strongly inhibits the aggregation of Aβ1‐42 as previously reported, but also interacts with the hydrophobic C‐terminus and middle domain of pEAβ3‐42 to maintain an unordered conformation, effectively impeding the formation of initial oligomers and subsequently halting the aggregation of pEAβ3‐42. Furthermore, TA can disrupt the "catalytic effect" of pEAβ3‐42 on amyloid aggregates, effectively suppressing Aβ aggregation and ultimately preventing the pathological events induced by Aβs. [ABSTRACT FROM AUTHOR]
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- 2024
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8. Transmembrane and coiled‐coil 2 associates with Alzheimer's disease pathology in the human brain.
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Hopkins, Paul C. R., Troakes, Claire, King, Andrew, and Tear, Guy
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AMYLOID beta-protein precursor , *ALZHEIMER'S disease , *TEMPORAL lobe , *AMYLOID plaque , *APOLIPOPROTEIN E - Abstract
Transmembrane and coiled‐coil 2 (TMCC2) is a human orthologue of the Drosophila gene dementin, mutant alleles of which cause neurodegeneration with features of Alzheimer's disease (AD). TMCC2 and Dementin further have an evolutionarily conserved interaction with the amyloid protein precursor (APP), a protein central to AD pathogenesis. To investigate if human TMCC2 might also participate in mechanisms of neurodegeneration, we examined TMCC2 expression in late onset AD human brain and age‐matched controls, familial AD cases bearing a mutation in APP Val717, and Down syndrome AD. Consistent with previous observations of complex formation between TMCC2 and APP in the rat brain, the dual immunocytochemistry of control human temporal cortex showed highly similar distributions of TMCC2 and APP. In late onset AD cases stratified by APOE genotype, TMCC2 immunoreactivity was associated with dense core senile plaques and adjacent neuronal dystrophies, but not with Aβ surrounding the core, diffuse Aβ plaques or tauopathy. In Down syndrome AD, we observed in addition TMCC2‐immunoreactive and methoxy‐X04‐positive pathological features that were morphologically distinct from those seen in the late onset and familial AD cases, suggesting enhanced pathological alteration of TMCC2 in Down syndrome AD. At the protein level, western blots of human brain extracts revealed that human brain‐derived TMCC2 exists as at least three isoforms, the relative abundance of which varied between the temporal gyrus and cerebellum and was influenced by APOE and/or dementia status. Our findings thus implicate human TMCC2 in AD via its interactions with APP, its association with dense core plaques, as well as its alteration in Down syndrome AD. [ABSTRACT FROM AUTHOR]
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- 2024
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9. Molecular basis of selective amyloid‐β degrading enzymes in Alzheimer's disease.
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Żukowska, Joanna, Moss, Stephen J., Subramanian, Vasanta, and Acharya, K. Ravi
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ALZHEIMER'S disease , *NEPRILYSIN , *ENDOTHELIN receptors , *ANGIOTENSIN I , *ENZYMES , *PEPTIDES , *AMYLOID plaque , *MOLECULAR structure - Abstract
The accumulation of the small 42‐residue long peptide amyloid‐β (Aβ) has been proposed as a major trigger for the development of Alzheimer's disease (AD). Within the brain, the concentration of Aβ peptide is tightly controlled through production and clearance mechanisms. Substantial experimental evidence now shows that reduced levels of Aβ clearance are present in individuals living with AD. This accumulation of Aβ can lead to the formation of large aggregated amyloid plaques—one of two detectable hallmarks of the disease. Aβ‐degrading enzymes (ADEs) are major players in the clearance of Aβ. Stimulating ADE activity or expression, in order to compensate for the decreased clearance in the AD phenotype, provides a promising therapeutic target. It has been reported in mice that upregulation of ADEs can reduce the levels of Aβ peptide and amyloid plaques—in some cases, this led to improved cognitive function. Among several known ADEs, neprilysin (NEP), endothelin‐converting enzyme‐1 (ECE‐1), insulin degrading enzyme (IDE) and angiotensin‐1 converting enzyme (ACE) from the zinc metalloprotease family have been identified as important. These ADEs have the capacity to digest soluble Aβ which, in turn, cannot form the toxic oligomeric species. While they are known for their amyloid degradation, they exhibit complexity through promiscuous nature and a broad range of substrates that they can degrade. This review highlights current structural and functional understanding of these key ADEs, giving some insight into the molecular interactions that leads to the hydrolysis of peptide substrates, the crucial tasks performed by them and the potential for therapeutic use in the future. [ABSTRACT FROM AUTHOR]
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- 2024
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10. Myeloid ectopic viral integration site 2 accelerates the progression of Alzheimer's disease.
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Cui, Yuting, Zhang, Xiaomin, Liu, Jing, Hou, Yuli, Song, Qiao, Cao, Min, Zhang, Jingjing, Wang, Xiaoling, Liu, Congcong, Wang, Peichang, and Wang, Yaqi
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ALZHEIMER'S disease , *AMYLOID beta-protein precursor , *TRANSCRIPTION factors , *AMYLOID plaque - Abstract
Amyloid plaques, a major pathological hallmark of Alzheimer's disease (AD), are caused by an imbalance between the amyloidogenic and non‐amyloidogenic pathways of amyloid precursor protein (APP). BACE1 cleavage of APP is the rate‐limiting step for amyloid‐β production and plaque formation in AD. Although the alteration of BACE1 expression in AD has been investigated, the underlying mechanisms remain unknown. In this study, we determined MEIS2 was notably elevated in AD models and AD patients. Alterations in the expression of MEIS2 can modulate the levels of BACE1. MEIS2 downregulation improved the learning and memory retention of AD mice and decreased the number of amyloid plaques. MEIS2 binds to the BACE1 promoter, positively regulates BACE1 expression, and accelerates APP amyloid degradation in vitro. Therefore, our findings suggest that MEIS2 might be a critical transcription factor in AD, since it regulates BACE1 expression and accelerates BACE1‐mediated APP amyloidogenic cleavage. MEIS2 is a promising early intervention target for AD treatment. [ABSTRACT FROM AUTHOR]
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- 2024
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11. Truncated GPNMB, a microglial transmembrane protein, serves as a scavenger receptor for oligomeric β‐amyloid peptide1‐42 in primary type 1 microglia.
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Kawahara, Kohichi, Hasegawa, Takuya, Hasegawa, Noa, Izumi, Taisei, Sato, Koji, Sakamaki, Toshiyuki, Ando, Masayuki, and Maeda, Takehiko
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MEMBRANE proteins , *MICROGLIA , *PLURIPOTENT stem cells , *AMYLOID plaque , *LIGANDS (Biochemistry) - Abstract
Glycoprotein non‐metastatic melanoma protein B (GPNMB) is up‐regulated in one subtype of microglia (MG) surrounding senile plaque depositions of amyloid‐beta (Aβ) peptides. However, whether the microglial GPNMB can recognize the fibrous Aβ peptides as ligands remains unknown. In this study, we report that the truncated form of GPNMB, the antigen for 9F5, serves as a scavenger receptor for oligomeric Aβ1‐42 (o‐Aβ1‐42) in rat primary type 1 MG. 125I‐labeled o‐Aβ1‐42 exhibited specific and saturable endosomal/lysosomal degradation in primary‐cultured type 1 MG from GPNMB‐expressing wild‐type mice, whereas the degradation activity was markedly reduced in cells from Gpnmb‐knockout mice. The Gpnmb‐siRNA significantly inhibits the degradation of 125I‐o‐Aβ1‐42 by murine microglial MG5 cells. Therefore, GPNMB contributes to mouse MG's o‐Aβ1‐42 clearance. In rat primary type 1 MG, the cell surface expression of truncated GPNMB was confirmed by a flow cytometric analysis using a previously established 9F5 antibody. 125I‐labeled o‐Aβ1‐42 underwent endosomal/lysosomal degradation by rat primary type 1 MG in a dose‐dependent fashion, while the 9F5 antibody inhibited the degradation. The binding of 125I‐o‐Aβ1‐42 to the rat primary type 1 MG was inhibited by 42% by excess unlabeled o‐Aβ1‐42, and by 52% by the 9F5 antibody. Interestingly, the 125I‐o‐Aβ1‐42 degradations by MG‐like cells from human‐induced pluripotent stem cells was inhibited by the 9F5 antibody, suggesting that truncated GPNMB also serve as a scavenger receptor for o‐Aβ1‐42 in human MG. Our study demonstrates that the truncated GPNMB (the antigen for 9F5) binds to oligomeric form of Aβ1‐42 and functions as a scavenger receptor on MG, and 9F5 antibody can act as a blocking antibody for the truncated GPNMB. [ABSTRACT FROM AUTHOR]
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- 2024
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12. Divergent Associations of Slow‐Wave Sleep versus Rapid Eye Movement Sleep with Plasma Amyloid‐Beta.
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Rosenblum, Yevgenia, Pereira, Mariana, Stange, Oliver, Weber, Frederik D., Bovy, Leonore, Tzioridou, Sofia, Lancini, Elisa, Neville, David A., Klein, Nadja, de Wolff, Timo, Stritzke, Mandy, Kersten, Iris, Uhr, Manfred, Claassen, Jurgen A. H. R., Steiger, Axel, Verbeek, Marcel M., and Dresler, Martin
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RAPID eye movement sleep , *SLOW wave sleep , *SLEEP stages , *SOMATOTROPIN , *AMYLOID plaque - Abstract
Objective: Recent evidence shows that during slow‐wave sleep (SWS), the brain is cleared from potentially toxic metabolites, such as the amyloid‐beta protein. Poor sleep or elevated cortisol levels can worsen amyloid‐beta clearance, potentially leading to the formation of amyloid plaques, a neuropathological hallmark of Alzheimer disease. Here, we explored how nocturnal neural and endocrine activity affects amyloid‐beta fluctuations in the peripheral blood. Methods: We acquired simultaneous polysomnography and all‐night blood sampling in 60 healthy volunteers aged 20–68 years. Nocturnal plasma concentrations of amyloid‐beta‐40, amyloid‐beta‐42, cortisol, and growth hormone were assessed every 20 minutes. Amyloid‐beta fluctuations were modeled with sleep stages, (non)oscillatory power, and hormones as predictors while controlling for age and participant‐specific random effects. Results: Amyloid‐beta‐40 and amyloid‐beta‐42 levels correlated positively with growth hormone concentrations, SWS proportion, and slow‐wave (0.3–4Hz) oscillatory and high‐band (30–48Hz) nonoscillatory power, but negatively with cortisol concentrations and rapid eye movement sleep (REM) proportion measured 40–100 minutes previously (all t values > |3|, p values < 0.003). Older participants showed higher amyloid‐beta‐40 levels. Interpretation: Slow‐wave oscillations are associated with higher plasma amyloid‐beta levels, whereas REM sleep is related to decreased amyloid‐beta plasma levels, possibly representing changes in central amyloid‐beta production or clearance. Strong associations between cortisol, growth hormone, and amyloid‐beta presumably reflect the sleep‐regulating role of the corresponding releasing hormones. A positive association between age and amyloid‐beta‐40 may indicate that peripheral clearance becomes less efficient with age. ANN NEUROL 2024;96:46–60 [ABSTRACT FROM AUTHOR]
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- 2024
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13. Molecular Dynamics and Binding Energetics of Fluspirilene With BACE1: Implications for Alzheimer's Disease Intervention.
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Bhattacharya, Kunal, Bhattacharjee, Atanu, Chakraborty, Manodeep, and Das, Dibyajyoti
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ALZHEIMER'S disease , *MOLECULAR docking , *MOLECULAR dynamics , *AMYLOID plaque , *MOLECULAR interactions , *NEURODEGENERATION - Abstract
Alzheimer's disease (AD) is a serious neurodegenerative disorder that results in cognitive deterioration, amnesia, and alterations in behavior, rendering it a significant issue in public health. The pathogenesis involves amyloid plaques highlighting the importance of targeting BACE1. This study explores fluspirilene, a di‐phenyl‐butyl‐piperidine as a potential BACE1 inhibitor for AD treatment. Fluspirilene was analyzed for ADMET. In silico molecular docking assessed fluspirilene's binding affinity with BACE1. Re‐docking a co‐crystallized ligand confirmed the docking process. Molecular dynamics simulations and related multifaceted computational analyses were conducted to assess the stability of docked complexes. Fluspirilene had good physicochemical and pharmacokinetic characteristics according to ADMET profiling. In silico molecular docking showed multiple BACE1 interactions with a binding affinity of −9.2 kcal/mol and fluspirilene–BACE1 complex stability was confirmed by molecular dynamics simulation results. Possible therapeutic applications in lowering Aβ generation and treating AD are indicated by the compound's pharmacokinetics, molecular interactions, and binding energetics. Validation and optimization of experiments are necessary for the clinical development of fluspirilene as a BACE1 inhibitor for AD. [ABSTRACT FROM AUTHOR]
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- 2024
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14. LATE‐NC in Alzheimer's disease: Molecular aspects and synergies.
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Tomé, Sandra O., Gawor, Klara, and Thal, Dietmar Rudolf
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ALZHEIMER'S disease , *FRONTOTEMPORAL lobar degeneration , *DEGENERATION (Pathology) , *NEUROFIBRILLARY tangles , *AMYLOID plaque - Abstract
Alzheimer's disease (AD) is classically characterized by senile plaques and neurofibrillary tangles (NFTs). However, multiple copathologies can be observed in the AD brain and contribute to the development of cognitive decline. Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological changes (LATE‐NC) accumulates in the majority of AD cases and leads to more severe cognitive decline compared with AD pathology alone. In this review, we focus on the synergistic relationship between LATE‐NC and tau in AD, highlighting the aggravating role of TDP‐43 aggregates on tau pathogenesis and its impact on the clinical picture and therapeutic strategies. Additionally, we discuss to what extent the molecular patterns of LATE‐NC in AD differ from frontotemporal lobar degeneration with TDP‐43 pathology (FTLD‐TDP) neuropathological changes. Thus, we highlight the importance of tau and TDP‐43 synergies for subtyping AD patients, which may respond differently to therapeutic interventions depending on the presence of comorbid LATE‐NC. [ABSTRACT FROM AUTHOR]
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- 2024
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15. Hybrid Membrane‐Coated Nanoparticles for Precise Targeting and Synergistic Therapy in Alzheimer's Disease.
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Lin, Rong‐Rong, Jin, Lu‐Lu, Xue, Yan‐Yan, Zhang, Zhe‐Sheng, Huang, Hui‐Feng, Chen, Dian‐Fu, Liu, Qian, Mao, Zheng‐Wei, Wu, Zhi‐Ying, and Tao, Qing‐Qing
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ALZHEIMER'S disease , *LIPOSOMES , *CHEMOKINE receptors , *TARGETED advertising , *NANOPARTICLES , *AMYLOID plaque , *NEUROLOGICAL disorders - Abstract
The blood brain barrier (BBB) limits the application of most therapeutic drugs for neurological diseases (NDs). Hybrid cell membrane‐coated nanoparticles derived from different cell types can mimic the surface properties and functionalities of the source cells, further enhancing their targeting precision and therapeutic efficacy. Neuroinflammation has been increasingly recognized as a critical factor in the pathogenesis of various NDs, especially Alzheimer's disease (AD). In this study, a novel cell membrane coating is designed by hybridizing the membrane from platelets and chemokine (C–C motif) receptor 2 (CCR2) cells are overexpressed to cross the BBB and target neuroinflammatory lesions. Past unsuccessful endeavors in AD drug development underscore the challenge of achieving favorable outcomes when utilizing single‐mechanism drugs.Two drugs with different mechanisms of actions into liposomes are successfully loaded to realize multitargeting treatment. In a transgenic mouse model for familial AD (5xFAD), the administration of these drug‐loaded hybrid cell membrane liposomes results in a significant reduction in amyloid plaque deposition, neuroinflammation, and cognitive impairments. Collectively, the hybrid cell membrane‐coated nanomaterials offer new opportunities for precise drug delivery and disease‐specific targeting, which represent a versatile platform for targeted therapy in AD. [ABSTRACT FROM AUTHOR]
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- 2024
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16. Pyrene Functionalized Norbornadiene‐Quadricyclane Fluorescent Photoswitches: Characterization of their Spectral Properties and Application in Imaging of Amyloid Beta Plaques.
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Ghasemi, Shima, Shamsabadi, Monika, Olesund, Axel, Najera, Francisco, Erbs Hillers‐Bendtsen, Andreas, Edhborg, Fredrik, Aslam, Adil S., Larsson, Wera, Wang, Zhihang, Amombo Noa, Francoise M., Salthouse, Rebecca Jane, Öhrström, Lars, Hölzel, Helen, Perez‐Inestrosa, E., Mikkelsen, Kurt V., Hanrieder, Jörg, Albinsson, Bo, Dreos, Ambra, and Moth‐Poulsen, Kasper
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AMYLOID plaque , *PYRENE , *DENSITY functional theory , *IRRADIATION , *EXCITED states , *ISOMERS - Abstract
This study presents the synthesis and characterization of two fluorescent norbornadiene (NBD) photoswitches, each incorporating two conjugated pyrene units. Expanding on the limited repertoire of reported photoswitchable fluorescent NBDs, we explore their properties with a focus on applications in bioimaging of amyloid beta (Aβ) plaques. While the fluorescence emission of the NBD decreases upon photoisomerization, aligning with what has been previously reported, for the first time we observed luminescence after irradiation of the quadricyclane (QC) isomer. We deduce how the observed emission is induced by photoisomerization to the excited state of the parent isomer (NBD) which is then the emitting species. Thorough characterizations including NMR, UV‐Vis, fluorescence, X‐ray structural analysis and density functional theory (DFT) calculations provide a comprehensive understanding of these systems. Notably, one NBD‐QC system exhibits exceptional durability. Additionally, these molecules serve as effective fluorescent stains targeting Aβ plaques in situ, with observed NBD/QC switching within the plaques. Molecular docking simulations explore NBD interactions with amyloid, unveiling novel binding modes. These insights mark a crucial advancement in the comprehension and design of future photochromic NBDs for bioimaging applications and beyond, emphasizing their potential in studying and addressing protein aggregates. [ABSTRACT FROM AUTHOR]
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- 2024
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17. Multi‐proteomic analyses of 5xFAD mice reveal new molecular signatures of early‐stage Alzheimer's disease.
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Lee, Seulah, Jang, Kuk‐In, Lee, Hagyeong, Jo, Yeon Suk, Kwon, Dayoung, Park, Geuna, Bae, Sungwon, Kwon, Yang Woo, Jang, Jin‐Hyeok, Oh, Yong‐Seok, Lee, Chany, and Yoon, Jong Hyuk
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ALZHEIMER'S disease , *MACHINE learning , *ALZHEIMER'S patients , *EXTRACELLULAR vesicles , *PRESENILINS , *AMYLOID plaque - Abstract
An early diagnosis of Alzheimer's disease is crucial as treatment efficacy is limited to the early stages. However, the current diagnostic methods are limited to mid or later stages of disease development owing to the limitations of clinical examinations and amyloid plaque imaging. Therefore, this study aimed to identify molecular signatures including blood plasma extracellular vesicle biomarker proteins associated with Alzheimer's disease to aid early‐stage diagnosis. The hippocampus, cortex, and blood plasma extracellular vesicles of 3‐ and 6‐month‐old 5xFAD mice were analyzed using quantitative proteomics. Subsequent bioinformatics and biochemical analyses were performed to compare the molecular signatures between wild type and 5xFAD mice across different brain regions and age groups to elucidate disease pathology. There was a unique signature of significantly altered proteins in the hippocampal and cortical proteomes of 3‐ and 6‐month‐old mice. The plasma extracellular vesicle proteomes exhibited distinct informatic features compared with the other proteomes. Furthermore, the regulation of several canonical pathways (including phosphatidylinositol 3‐kinase/protein kinase B signaling) differed between the hippocampus and cortex. Twelve potential biomarkers for the detection of early‐stage Alzheimer's disease were identified and validated using plasma extracellular vesicles from stage‐divided patients. Finally, integrin α‐IIb, creatine kinase M‐type, filamin C, glutamine γ‐glutamyltransferase 2, and lysosomal α‐mannosidase were selected as distinguishing biomarkers for healthy individuals and early‐stage Alzheimer's disease patients using machine learning modeling with approximately 79% accuracy. Our study identified novel early‐stage molecular signatures associated with the progression of Alzheimer's disease, thereby providing novel insights into its pathogenesis. [ABSTRACT FROM AUTHOR]
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- 2024
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18. Timing of Biomarker Changes in Sporadic Alzheimer's Disease in Estimated Years from Symptom Onset.
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Li, Yan, Yen, Daniel, Hendrix, Rachel D., Gordon, Brian A., Dlamini, Sibonginkhosi, Barthélemy, Nicolas R., Aschenbrenner, Andrew J., Henson, Rachel L., Herries, Elizabeth M., Volluz, Katherine, Kirmess, Kristopher, Eastwood, Stephanie, Meyer, Matthew, Heller, Maren, Jarrett, Lea, McDade, Eric, Holtzman, David M., Benzinger, Tammie L.S., Morris, John C., and Bateman, Randall J.
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ALZHEIMER'S disease , *POSITRON emission tomography , *BIOMARKERS , *CEREBRAL amyloid angiopathy , *AMYLOID plaque , *SYMPTOMS - Abstract
Objective: A clock relating amyloid positron emission tomography (PET) to time was used to estimate the timing of biomarker changes in sporadic Alzheimer disease (AD). Methods: Research participants were included who underwent cerebrospinal fluid (CSF) collection within 2 years of amyloid PET. The ages at amyloid onset and AD symptom onset were estimated for each individual. The timing of change for plasma, CSF, imaging, and cognitive measures was calculated by comparing restricted cubic splines of cross‐sectional data from the amyloid PET positive and negative groups. Results: The amyloid PET positive sub‐cohort (n = 118) had an average age of 70.4 ± 7.4 years (mean ± standard deviation) and 16% were cognitively impaired. The amyloid PET negative sub‐cohort (n = 277) included individuals with low levels of amyloid plaque burden at all scans who were cognitively unimpaired at the time of the scans. Biomarker changes were detected 15–19 years before estimated symptom onset for CSF Aβ42/Aβ40, plasma Aβ42/Aβ40, CSF pT217/T217, and amyloid PET; 12–14 years before estimated symptom onset for plasma pT217/T217, CSF neurogranin, CSF SNAP‐25, CSF sTREM2, plasma GFAP, and plasma NfL; and 7–9 years before estimated symptom onset for CSF pT205/T205, CSF YKL‐40, hippocampal volumes, and cognitive measures. Interpretation: The use of an amyloid clock enabled visualization and analysis of biomarker changes as a function of estimated years from symptom onset in sporadic AD. This study demonstrates that estimated years from symptom onset based on an amyloid clock can be used as a continuous staging measure for sporadic AD and aligns with findings in autosomal dominant AD. ANN NEUROL 2024;95:951–965 [ABSTRACT FROM AUTHOR]
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- 2024
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19. Association between hypothalamic Alzheimer's disease pathology and body mass index: The Hisayama study.
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Yagita, Kaoru, Honda, Hiroyuki, Ohara, Tomoyuki, Koyama, Sachiko, Noguchi, Hideko, Oda, Yoshinao, Yamasaki, Ryo, Isobe, Noriko, and Ninomiya, Toshiharu
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The hypothalamus is the region of the brain that integrates the neuroendocrine system and whole‐body metabolism. Patients with Alzheimer's disease (AD) have been reported to exhibit pathological changes in the hypothalamus, such as neurofibrillary tangles (NFTs) and amyloid plaques (APs). However, few studies have investigated whether hypothalamic AD pathology is associated with clinical factors. We investigated the association between AD‐related pathological changes in the hypothalamus and clinical pictures using autopsied brain samples obtained from deceased residents of a Japanese community. A total of 85 autopsied brain samples were semi‐quantitatively analyzed for AD pathology, including NFTs and APs. Our histopathological studies showed that several hypothalamic nuclei, such as the tuberomammillary nucleus (TBM) and lateral hypothalamic area (LHA), are vulnerable to AD pathologies. NFTs are observed in various neuropathological states, including normal cognitive cases, whereas APs are predominantly observed in AD. Regarding the association between hypothalamic AD pathologies and clinical factors, the degree of APs in the TBM and LHA was associated with a lower body mass index while alive, after adjusting for sex and age at death. However, we found no significant association between hypothalamic AD pathology and the prevalence of hypertension, diabetes, or dyslipidemia. Our study showed that a lower BMI, which is a poor prognostic factor of AD, might be associated with hypothalamic AP pathology and highlighted new insights regarding the disruption of the brain–whole body axis in AD. [ABSTRACT FROM AUTHOR]
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- 2024
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20. Data‐driven stochastic model for quantifying the interplay between amyloid‐beta and calcium levels in Alzheimer's disease.
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Shaheen, Hina, Melnik, Roderick, and Singh, Sundeep
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ALZHEIMER'S disease , *HOMEOSTASIS , *STOCHASTIC models , *AMYLOID plaque , *CALCIUM - Abstract
The abnormal aggregation of extracellular amyloid‐β(Aβ)$$ \left(A\beta \right) $$ in senile plaques resulting in calcium Ca+2$$ \left({Ca}^{+2}\right) $$ dyshomeostasis is one of the primary symptoms of Alzheimer's disease (AD). Significant research efforts have been devoted in the past to better understand the underlying molecular mechanisms driving Aβ$$ A\beta $$ deposition and Ca+2$$ {Ca}^{+2} $$ dysregulation. Importantly, synaptic impairments, neuronal loss, and cognitive failure in AD patients are all related to the buildup of intraneuronal Aβ$$ A\beta $$ accumulation. Moreover, increasing evidence show a feed‐forward loop between Aβ$$ A\beta $$ and Ca+2$$ {Ca}^{+2} $$ levels, that is, Aβ$$ A\beta $$ disrupts neuronal Ca+2$$ {Ca}^{+2} $$ levels, which in turn affects the formation of Aβ$$ A\beta $$. To better understand this interaction, we report a novel stochastic model where we analyze the positive feedback loop between Aβ$$ A\beta $$ and Ca+2$$ {Ca}^{+2} $$ using ADNI data. A good therapeutic treatment plan for AD requires precise predictions. Stochastic models offer an appropriate framework for modeling AD since AD studies are observational in nature and involve regular patient visits. The etiology of AD may be described as a multi‐state disease process using the approximate Bayesian computation method. So, utilizing ADNI data from 2$$ 2 $$‐year visits for AD patients, we employ this method to investigate the interplay between Aβ$$ A\beta $$ and Ca+2$$ {Ca}^{+2} $$ levels at various disease development phases. Incorporating the ADNI data in our physics‐based Bayesian model, we discovered that a sufficiently large disruption in either Aβ$$ A\beta $$ metabolism or intracellular Ca+2$$ {Ca}^{+2} $$ homeostasis causes the relative growth rate in both Ca+2$$ {Ca}^{+2} $$ and Aβ$$ A\beta $$, which corresponds to the development of AD. The imbalance of Ca+2$$ {Ca}^{+2} $$ ions causes Aβ$$ A\beta $$ disorders by directly or indirectly affecting a variety of cellular and subcellular processes, and the altered homeostasis may worsen the abnormalities of Ca+2$$ {Ca}^{+2} $$ ion transportation and deposition. This suggests that altering the Ca+2$$ {Ca}^{+2} $$ balance or the balance between Aβ$$ A\beta $$ and Ca+2$$ {Ca}^{+2} $$ by chelating them may be able to reduce disorders associated with AD and open up new research possibilities for AD therapy. [ABSTRACT FROM AUTHOR]
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- 2024
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21. Dynamic changes in lysosome‐related pathways in APP/PS1 mice with aging.
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Xu, Zhendong, Hu, Jichang, Wei, Zhen, Lei, Yu, Afewerky, Henok Kessete, Gao, Yang, Wan, Lu, Li, Longfei, Lei, Ling, Liu, Yi, Huang, Fang, Yu, Tong, Wang, Jian‐Zhi, Li, Hong‐Lian, Liu, Rong, and Wang, Xiaochuan
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MOLECULAR biology ,ALZHEIMER'S disease ,PROTEIN precursors ,AMYLOID plaque ,MICE - Abstract
Senile plaque, composed of amyloid β protein (Aβ) aggregates, is a critical pathological feature in Alzheimer's disease (AD), leading to cognitive dysfunction. However, how Aβ aggregates exert age‐dependent toxicity and temporal cognitive dysfunction in APP/PS1 mice remains incompletely understood. In this study, we investigated AD pathogenesis and dynamic alterations in lysosomal pathways within the hippocampus of age‐gradient male mice using transcriptome sequencing, molecular biology assays, and histopathological analyses. We observed high levels of β‐amyloid precursor protein (APP) protein expression in the hippocampus at an early stage and age‐dependent Aβ deposition. Transcriptome sequencing revealed the enrichment of differential genes related to the lysosome pathway. Furthermore, the protein expression of ATP6V0d2 and CTSD associated with lysosomal functions exhibited dynamic changes with age, increasing in the early stage and decreasing later. Similar age‐dependent patterns were observed for the endosome function, autophagy pathway, and SGK1/FOXO3a pathway. Nissl and Golgi staining in the hippocampal region showed age‐dependent neuronal loss and synaptic damage, respectively. These findings clearly define the age‐gradient changes in the autophagy–lysosome system, the endosome/lysosome system, and the SGK1/FOXO3a pathway in the hippocampus of APP/PS1 mice, providing new perspectives and clues for understanding the possible mechanisms of AD, especially the transition from compensatory to decompensated state. [ABSTRACT FROM AUTHOR]
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- 2024
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22. Detecting time‐varying genetic effects in Alzheimer's disease using a longitudinal genome‐wide association studies model.
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Zhuang, Xiaowei, Xu, Gang, Amei, Amei, Cordes, Dietmar, Wang, Zuoheng, and Oh, Edwin C.
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GENOME-wide association studies ,ALZHEIMER'S disease ,POSITRON emission tomography ,SINGLE nucleotide polymorphisms ,AMYLOID plaque ,PHENOTYPES - Abstract
INTRODUCTION: The development and progression of Alzheimer's disease (AD) is a complex process, during which genetic influences on phenotypes may also change. Incorporating longitudinal phenotypes in genome‐wide association studies (GWAS) could unmask these genetic loci. METHODS: We conducted a longitudinal GWAS using a varying coefficient test to identify age‐dependent single nucleotide polymorphisms (SNPs) in AD. Data from 1877 Alzheimer's Neuroimaging Data Initiative participants, including impairment status and amyloid positron emission tomography (PET) scan standardized uptake value ratio (SUVR) scores, were analyzed using a retrospective varying coefficient mixed model association test (RVMMAT). RESULTS: RVMMAT identified 244 SNPs with significant time‐varying effects on AD impairment status, with 12 SNPs on chromosome 19 validated using National Alzheimer's Coordinating Center data. Age‐stratified analyses showed these SNPs' effects peaked between 70 and 80 years. Additionally, 73 SNPs were linked to longitudinal amyloid accumulation changes. Pathway analyses implicated immune and neuroinflammation‐related disruptions. DISCUSSION: Our findings demonstrate that longitudinal GWAS models can uncover time‐varying genetic signals in AD. Highlights: Identify time‐varying genetic effects using a longitudinal GWAS model in AD.Illustrate age‐dependent genetic effects on both diagnoses and amyloid accumulation.Replicate time‐varying effect of APOE in a second dataset. [ABSTRACT FROM AUTHOR]
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- 2024
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23. FF Activates Nucleation for Aggregation in Aqueous Medium: A Key Insight of Amyloid Plaque Formation.
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Roy, Sruti Singha, Ghosh, Ria, Mukherjee, Dipanjan, Biswas, Swagata, Pal, Samir Kumar, and Banerjee, Raja
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NUCLEATION , *AMYLOID plaque , *ALZHEIMER'S patients , *ALZHEIMER'S disease , *AMYLOID , *PROTEIN folding - Abstract
Molecular self‐association of monomers with multifaceted cross‐linkers, opens new possibilities for the development of various supramolecular‐networks that enable to participate in different functions. Plaques associated with senility that form in the brains of Alzheimer′s patients are mainly composed of beta amyloid (Aβ). It can be assumed that there must be a nucleation site which through reverse folding initiate to aggregate this Aβ plaque. It has been reported KLVFFA motif of Aβ sequence plays an important role as the amylogenic unit for Alzheimer disease. In order to identify the shortest sequence that would initiate the nucleation for such aggregation, we have synthesized N‐terminal protected two two‐residue peptides [Hex‐Phe(1)‐Phe(2)‐OMe: (FF)] and [Hex‐Phe(1)‐Ala(2)‐OMe: (FA)] an important fragment of KLVFFA motif. Using various microscopic and biophysical approaches, including measuring the hydrodynamic radii, it is observed that in fully aqueous condition in comparison to FA, FF nucleates higher degree of aggregates, along with substantial formation of dendrimeric amyloid fibrils, which has been elegantly visualized in Congo‐red assay through formation of distinct apple‐green birefringence. Such an observation leads to hypothesize that the 'di‐phenylalanine' unit (FF) plays a crucial role as the nucleation site towards attaining the aggregate for formation of the Aβ plaque through reverse folding. [ABSTRACT FROM AUTHOR]
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- 2024
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24. The Tao Hong Si Wu Decoction ameliorates diabetes‐associated cognitive dysfunction by inhibiting the formation of amyloid plaques.
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Cai, Ming, Chen, Zhen, Zhang, Mengling, Xia, Wenwen, Dai, Wentao, Zhao, Mengdie, Xie, Ruonan, Ji, Zhaojie, Han, Lan, and Peng, Daiyin
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DIABETES complications , *CHINESE medicine , *BIOLOGICAL models , *PROTEIN precursors , *GLYCOSYLATED hemoglobin , *PHOSPHORYLATION , *T-test (Statistics) , *STATISTICAL significance , *HERBAL medicine , *LIPIDS , *TREATMENT effectiveness , *LEARNING , *DESCRIPTIVE statistics , *RATS , *COGNITION disorders , *AMYLOID plaque , *ANIMAL experimentation , *LIQUID chromatography , *WESTERN immunoblotting , *MEMORY , *PROTEOLYTIC enzymes , *ADVANCED glycation end-products , *AMINOGLYCOSIDES , *HIPPOCAMPUS (Brain) , *FACTOR analysis , *THERAPEUTICS - Abstract
Objectives: The herbs in Tao Hong Si Wu Decoction (THSWD) are beneficial in the treatment of cognitive impairment. However, the underlying mechanisms of THSWD in treating diabetes‐associated cognitive dysfunction (DACD) are not entirely explored. This study is aimed to investigate the therapeutic effects of THSWD in DACD model rats and the underlying mechanism. Methods: Ultra‐high‐phase liquid chromatography was employed to identify the main compounds contained in the THSWD extract. DACD rat model was induced by feeding with a high‐sugar and high‐fat diet and injecting streptozotocin (35 mg/kg). DACD rats were gavaged with THSWD for 1 week. The learning and memory abilities of the rats were measured by using the Morris water maze. Western blotting was used to detect the changes in DACD rat targets. Statistical methods were used to evaluate the correlation between proteins. Results: The results show that THSWD effectively reduced the escape latency, hippocampal neuron damage, glycosylated hemoglobin, type A1C, and blood lipid levels in DACD rats. Furthermore, DACD rats showed significantly increased amyloid precursor protein, β‐secretase, Aβ1−40, Aβ1−42, Tau phosphorylation, and advanced glycation end products (AGEs) expression. However, THSWD treatment can reverse this phenomenon. Conclusions: THSWD can improve the learning and memory abilities of DACD rats by inhibiting the expression of AEGs‐AGE receptors pathway, which provides an experimental basis for the clinical application of THSWD. In addition, the experiment combines pharmacological and statistical methods, which offers a new perspective for the study of Chinese herbal medicine. Key points: Tao Hong Si Wu Decoction (THSWD) can improve the learning and memory abilities of diabetes‐associated cognitive dysfunction (DACD) rats.Reduced Aβ content was associated with more favorable cognitive abilities.The advanced glycation end products (AGEs)‐AGE receptors (RAGE) pathway may be a key pathway for THSWD to alleviate symptoms in DACD rats and exert therapeutic effects. [ABSTRACT FROM AUTHOR]
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- 2024
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25. Diagnostic value of CSF chromogranin A to discriminate between Alzheimer's disease and dementia with Lewy bodies.
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Bousiges, Olivier, Lavaux, Thomas, Demuynck, Catherine, Schaeffer‐Agalède, Caroline, Philippi, Nathalie, Muller, Candice, Cretin, Benjamin, and Blanc, Frédéric
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CEREBROSPINAL fluid examination , *ALZHEIMER'S disease , *LEWY body dementia , *AMYLOID plaque , *CEREBROSPINAL fluid , *TAUOPATHIES - Abstract
Background: Chromogranin A (CgA) seems to be involved in the pathophysiology of different neurodegenerative pathologies such as Alzheimer's disease (AD) and dementia with Lewy Bodies (DLB). CgA is present in the aggregates of amyloid plaques and in Lewy bodies but CgA also has a function in neuroinflammatory processes via microglia. Our objective was to determine if there is a difference in the CgA concentration in the cerebrospinal fluid (CSF) of AD and DLB patients and whether the CgA concentration can discriminate between the two diseases. Methods: Using the previously described AlphaLewyMA cohort, we included 117 patients with a CSF CgA assay: 15 control subjects (CS group), 64 DLB patients, 17 AD patients and 21 patients with both AD and probable DLB criteria (AD/DLB group). CgA concentration was assessed using the MSD platform. Results: CSF CgA was increased in the AD and AD/DLB groups compared with the DLB group (p = 0.0006 between AD and DLB, p = 0.0013 between AD/DLB and DLB). No significant difference in CgA concentration was found between DLB and CS. ROC curve analysis showed an area under the curve of 0.791 between AD and DLB. CgA concentrations were correlated with t‐Tau and P‐Tau regardless of the pathology (for Tau: p = 0.022 for AD; p < 0.0001 for DLB; p = 0.004 for AD/DLB; for P‐Tau: p = 0.032 for AD; p < 0.0001 for DLB; p = 0.0009 for AD/DLB). Aβ42 was positively correlated with CgA in the DLB group but not in the AD and AD/DLB groups (for DLB: p < 0.0001; for AD: p = 0.57; for AD/DLB: p = 0.58). Conclusions: CSF CgA concentrations are increased in AD but not in DLB and correlate with P‐Tau and Tau whatever the disease. These results suggest a link between tauopathy/neurodegeneration and CgA. [ABSTRACT FROM AUTHOR]
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- 2024
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26. Cellular iron depletion enhances behavioral rhythm by limiting brain Per1 expression in mice.
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Wu, Qiong, Ren, Qiuyang, Wang, Xin, Bai, Huiyuan, Tian, Dandan, Gao, Guofen, Wang, Fudi, Yu, Peng, and Chang, Yan‐Zhong
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IRON , *BRAIN waves , *AMYLOID plaque , *MOLECULAR clock , *CLOCK genes , *IRON chelates - Abstract
Aims: Disturbances in the circadian rhythm are positively correlated with the processes of aging and related neurodegenerative diseases, which are also associated with brain iron accumulation. However, the role of brain iron in regulating the biological rhythm is poorly understood. In this study, we investigated the impact of brain iron levels on the spontaneous locomotor activity of mice with altered brain iron levels and further explored the potential mechanisms governing these effects in vitro. Results: Our results revealed that conditional knockout of ferroportin 1 (Fpn1) in cerebral microvascular endothelial cells led to brain iron deficiency, subsequently resulting in enhanced locomotor activity and increased expression of clock genes, including the circadian locomotor output cycles kaput protein (Clock) and brain and muscle ARNT‐like 1 (Bmal1). Concomitantly, the levels of period circadian regulator 1 (PER1), which functions as a transcriptional repressor in regulating biological rhythm, were decreased. Conversely, the elevated brain iron levels in APP/PS1 mice inhibited autonomous rhythmic activity. Additionally, our findings demonstrate a significant decrease in serum melatonin levels in Fpn1cdh5 ‐CKO mice compared with the Fpn1flox/flox group. In contrast, APP/PS1 mice with brain iron deposition exhibited higher serum melatonin levels than the WT group. Furthermore, in the human glioma cell line, U251, we observed reduced PER1 expression upon iron limitation by deferoxamine (DFO; iron chelator) or endogenous overexpression of FPN1. When U251 cells were made iron‐replete by supplementation with ferric ammonium citrate (FAC) or increased iron import through transferrin receptor 1 (TfR1) overexpression, PER1 protein levels were increased. Additionally, we obtained similar results to U251 cells in mouse cerebellar astrocytes (MA‐c), where we collected cells at different time points to investigate the rhythmic expression of core clock genes and the impact of DFO or FAC treatment on PER1 protein levels. Conclusion: These findings collectively suggest that altered iron levels influence the circadian rhythm by regulating PER1 expression and thereby modulating the molecular circadian clock. In conclusion, our study identifies the regulation of brain iron levels as a potential new target for treating age‐related disruptions in the circadian rhythm. [ABSTRACT FROM AUTHOR]
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- 2024
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27. Autonomous animal heating and cooling system for temperature‐regulated magnetic resonance experiments.
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Verghese, George, Vöröslakos, Mihaly, Markovic, Stefan, Tal, Assaf, Dehkharghani, Seena, Yaghmazadeh, Omid, and Alon, Leeor
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MAGNETIC resonance ,COOLING systems ,PHYSIOLOGY ,SPECTROSCOPIC imaging ,HEATING ,THERMISTORS ,AMYLOID plaque - Abstract
Temperature is a hallmark parameter influencing almost all magnetic resonance properties (e.g., T1, T2, proton density, and diffusion). In the preclinical setting, temperature has a large influence on animal physiology (e.g., respiration rate, heart rate, metabolism, and oxidative stress) and needs to be carefully regulated, especially when the animal is under anesthesia and thermoregulation is disrupted. We present an open‐source heating and cooling system capable of regulating the temperature of the animal. The system was designed using Peltier modules capable of heating or cooling a circulating water bath with active temperature feedback. Feedback was obtained using a commercial thermistor, placed in the animal rectum, and a proportional‐integral‐derivative controller was used to modulate the temperature. Its operation was demonstrated in a phantom as well as in mouse and rat animal models, where the standard deviation of the temperature of the animal upon convergence was less than a 10th of a degree. An application where brain temperature of a mouse was modulated was demonstrated using an invasive optical probe and noninvasive magnetic resonance spectroscopic thermometry measurements. [ABSTRACT FROM AUTHOR]
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- 2024
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28. Oral manifestations of amyloidosis and the diagnostic applicability of oral tissue biopsy.
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Tavares, Thalita Soares, da Costa, Adriana Aparecida Silva, Araújo, Anna Luíza Damaceno, de Souza, Lucas Lacerda, Pascoaloti, Maria Inês Mantuani, Bernardes, Vanessa Fátima, Aguiar, Maria Cássia Ferreira, Vargas, Pablo Agustin, Fonseca, Felipe Paiva, Pontes, Hélder Antônio Rebelo, Lopes, Marcio Ajudarte, Santos‐Silva, Alan Roger, da Silva, Tarcília Aparecida, and Caldeira, Patrícia Carlos
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ORAL manifestations of general diseases , *AMYLOIDOSIS , *AMYLOID plaque , *BIOPSY , *FAT cells , *CARDIAC amyloidosis - Abstract
Background: Amyloidosis exhibits a variable spectrum of systemic signs and oral manifestations that can be difficult to diagnose. This study aimed to characterize the clinical, demographic, and microscopic features of amyloidosis in the oral cavity. Methods: This collaborative study involved three Brazilian oral pathology centers and described cases with a confirmed diagnosis of amyloidosis on available oral tissue biopsies. Clinical data were obtained from medical records. H&E, Congo‐red, and immunohistochemically stained slides were analyzed. Results: Twenty‐six oral biopsies from 23 individuals (65.2% males; mean age: 59.6 years) were included. Oral involvement was the first sign of the disease in 67.0% of cases. Two patients had no clinical manifestation in the oral mucosa, although the histological analysis confirmed amyloid deposition. Amyloid deposits were distributed in perivascular (88.0%), periacinar and periductal (80.0%), perineurial (80.0%), endoneurial (33.3%), perimuscular (88.2%), intramuscular (94.1%), and subepithelial (35.3%) sites as well as around fat cells (100.0%). Mild/moderate inflammation was found in 65.4% of cases and 23.1% had giant cells. Conclusions: Amyloid deposits were consistently found in oral tissues, exhibiting distinct deposition patterns. Oral biopsy is less invasive than internal organ biopsy and enables the reliable identification of amyloid deposits even in the absence of oral manifestations. These findings corroborate the relevance of oral biopsy for the diagnosis of amyloidosis. [ABSTRACT FROM AUTHOR]
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- 2024
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29. Delayed primacy recall performance predicts post mortem Alzheimer's disease pathology from unimpaired ante mortem cognitive baseline.
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Bruno, Davide, Gicas, Kristina M., Jauregi‐Zinkunegi, Ainara, Mueller, Kimberly D., and Lamar, Melissa
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ALZHEIMER'S disease ,PATHOLOGY ,AMYLOID plaque ,NEUROFIBRILLARY tangles ,APOLIPOPROTEIN E - Abstract
We propose a novel method to assess delayed primacy in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) memory test. We then examine whether this measure predicts post mortem Alzheimer's disease (AD) neuropathology in individuals who were clinically unimpaired at baseline. A total of 1096 individuals were selected from the Rush Alzheimer's Disease Center database registry. All participants were clinically unimpaired at baseline, and had subsequently undergone brain autopsy. Average age at baseline was 78.8 (6.92). A Bayesian regression analysis was carried out with global pathology as an outcome; demographic, clinical, and apolipoprotein E (APOE) data as covariates; and cognitive predictors, including delayed primacy. Global AD pathology was best predicted by delayed primacy. Secondary analyses showed that delayed primacy was mostly associated with neuritic plaques, whereas total delayed recall was associated with neurofibrillary tangles. Sex differential associations were observed. We conclude that CERAD‐derived delayed primacy is a useful metric for early detection and diagnosis of AD in unimpaired individuals. Highlights: We propose a novel method to analyse serial position in the CERAD memory test.We analyse data from 1096 individuals who were cognitively unimpaired at baseline.Delayed primacy predicts post mortem pathology better than traditional metrics. [ABSTRACT FROM AUTHOR]
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- 2024
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30. Bone Marrow‐Derived GCA+ Immune Cells Drive Alzheimer's Disease Progression.
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Zhou, Rui, Wang, Liwen, Chen, Linyun, Feng, Xu, Zhou, Ruoyu, Xiang, Peng, Wen, Jie, Huang, Yan, and Zhou, Haiyan
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ALZHEIMER'S disease , *DISEASE progression , *BONE marrow cells , *CENTRAL nervous system diseases , *AMYLOID plaque - Abstract
Alzheimer's disease (AD) is an age‐related degenerative disease of the central nervous system (CNS), whereas the role of bone marrow immune cells in the pathogenesis of AD remains unclear. Here, the study reveals that compared to matched healthy individuals, AD patients have higher circulating grancalcin (GCA) levels, which negatively correlate with cognitive function. Bone marrow‐derived GCA+ immune cells, which secret abundant GCA and increase during aging, preferentially invaded the hippocampus and cortex of AD mouse model in a C‐C Motif Chemokine Receptor 10 (CCR10)‐dependent manner. Transplanting GCA+ immune cells or direct stereotaxic injection of recombinant GCA protein intensified amyloid plaque load and aggravated cognitive and memory impairments. In contrast, genetic ablation of GCA in the hematopoietic compartment improves cognitive and memory function. Mechanistically, GCA competitively binds to the low‐density lipoprotein receptor‐related protein 1 (LRP1) in microglia, thus inhibiting phagocytosis and clearance of Aβ and potentiating neuropathological changes. Importantly, GCA‐neutralizing antibody treatment rejuvenated cognitive and memory function and constrained AD progression. Together, the study demonstrates a pathological role of GCA+ immune cells instigating cognitive and memory decline, suggesting that GCA+ immune cells can be a potential target for innovative therapeutic strategies in AD. [ABSTRACT FROM AUTHOR]
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- 2023
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31. Chemical Imaging of RNA‐Tau Amyloid Fibrils at the Nanoscale Using Tip‐Enhanced Raman Spectroscopy.
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Cooney, Gary Sean, Talaga, David, Ury‐Thiery, Vicky, Fichou, Yann, Huang, Yuhan, Lecomte, Sophie, and Bonhommeau, Sébastien
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RAMAN spectroscopy , *AMYLOID , *TAU proteins , *ADENINE , *COAT proteins (Viruses) , *SERS spectroscopy , *AMYLOID plaque - Abstract
In the presence of cofactors, tau protein can form amyloid deposits in the brain which are implicated in many neurodegenerative disorders. Heparin, lipids, and RNA are used to recreate tau aggregates in vitro from recombinant protein. However, the mechanism of interaction of these cofactors and the interactions between cofactors and tau are poorly understood. Herein, we use tip‐enhanced Raman spectroscopy (TERS) to visualize the spatial distribution of adenine, protein secondary structure, and amino acids (arginine, lysine and histidine) in single polyadenosine (polyA)‐induced tau fibrils with nanoscale spatial resolution (<10–20 nm). Based on reference unenhanced and surface‐enhanced Raman spectra, we show that the polyA anionic cofactor is incorporated in the fibril structure and seems to be superficial to the β‐sheet core, but nonetheless enveloped within the random‐coiled fuzzy coat. TERS images also prove the colocalization of positively charged arginine, lysine, and histidine amino acids and negatively charged polyA, which constitutes an important step forward to better comprehend the action of RNA cofactors in the mechanism of formation of toxic tau fibrils. TERS appears as a powerful technique for the identification of cofactors in individual tau fibrils and their mode of interaction. [ABSTRACT FROM AUTHOR]
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- 2023
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32. Carbamate as a potential anti‐Alzheimer's pharmacophore: A review.
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Singh, Yash Pal, Kumar, Navneet, Chauhan, Brijesh Singh, and Garg, Prabha
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ALZHEIMER'S disease , *AMYLOID plaque , *ACETYLCHOLINESTERASE inhibitors , *METHYL aspartate receptors , *RIVASTIGMINE , *MUSCARINIC receptors , *PHARMACOPHORE - Abstract
Alzheimer's disease (AD) is a progressive age‐related neurodegenerative brain disorder, which leads to loss of memory and other cognitive dysfunction. The underlying mechanisms of AD pathogenesis are very complex and still not fully explored. Cholinergic neuronal loss, accumulation of amyloid plaque, metal ions dyshomeostasis, tau hyperphosphorylation, oxidative stress, neuroinflammation, and mitochondrial dysfunction are major hallmarks of AD. The current treatment options for AD are acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and NMDA receptor antagonists (memantine). These FDA‐approved drugs mainly provide symptomatic relief without addressing the pathological aspects of disease progression. So, there is an urgent need for novel drug development that not only addresses the basic mechanisms of the disease but also shows the neuroprotective property. Various research groups across the globe are working on the development of multifunctional agents for AD amelioration using different core scaffolds for their design, and carbamate is among them. Rivastigmine was the first carbamate drug investigated for AD management. The carbamate fragment, a core scaffold of rivastigmine, act as a potential inhibitor of acetylcholinesterase. In this review, we summarize the last 10 years of research conducted on the modification of carbamate with different substituents which primarily target ChE inhibition, reduce oxidative stress, and modulate Aβ aggregation. [ABSTRACT FROM AUTHOR]
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- 2023
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33. APOE ε4's impact on response to amyloid therapies in early symptomatic Alzheimer's disease: Analyses from multiple clinical trials.
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Evans, Cynthia D., Sparks, JonDavid, Andersen, Scott W., Brooks, Dawn A., Hauck, Paula M., Mintun, Mark A., and Sims, John R.
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INTRODUCTION: Apolipoprotein E (APOE) ε4 may interact with response to amyloid‐targeting therapies. METHODS: Aggregate data from trials enrolling participants with amyloid‐positive, early symptomatic Alzheimer's disease (AD) were analyzed for disease progression. RESULTS: Pooled analysis of potentially efficacious antibodies lecanemab, aducanumab, solanezumab, and donanemab shows slightly better efficacy in APOE ε4 carriers than in non‐carriers. Carrier and non‐carrier mean (95% confidence interval) differences from placebo using Clinical Dementia Rating Scale–Sum of Boxes (CDR‐SB) were –0.30 (–0.478, –0.106) and –0.20 (–0.435, 0.042) and AD Assessment Scale–Cognitive subscale (ADAS‐Cog) values were –1.01 (–1.577, –0.456) and –0.80 (–1.627, 0.018), respectively. Decline in the APOE ε4 non‐carrier placebo group was equal to or greater than that in carriers across multiple scales. Probability of study success increases as the representation of the carrier population increases. DISCUSSION: We hypothesize that APOE ε4 carriers have same or better response than non‐carriers to amyloid‐targeting therapies and similar or less disease progression with placebo in amyloid‐positive trials. HIGHLIGHTS: Amyloid‐targeting therapies had slightly greater efficacy in apolipoprotein E (APOE) ε4 carriers.Clinical decline is the same/slightly faster in amyloid‐positive APOE ε4 non‐carriers.Prevalence of non‐carriers in trial populations could impact outcomes. [ABSTRACT FROM AUTHOR]
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- 2023
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34. Myelination‐ and migration‐associated genes are downregulated after phagocytosis in cultured oligodendrocyte precursor cells.
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Hamanaka, Gen, Hernández, Iván Coto, Takase, Hajime, Ishikawa, Hidehiro, Benboujja, Fouzi, Kimura, Shintaro, Fukuda, Norito, Guo, Shuzhen, Lok, Josephine, Lo, Eng H., and Arai, Ken
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PHAGOCYTOSIS , *MYELIN proteins , *NEUROGLIA , *CENTRAL nervous system , *AMYLOID plaque , *CORPUS callosum - Abstract
In the central nervous system, microglia are responsible for removing infectious agents, damaged/dead cells, and amyloid plaques by phagocytosis. Other cell types, such as astrocytes, are also recently recognized to show phagocytotic activity under some conditions. Oligodendrocyte precursor cells (OPCs), which belong to the same glial cell family as microglia and astrocytes, may have similar functions. However, it remains largely unknown whether OPCs exhibit phagocytic activity against foreign materials like microglia. To answer this question, we examined the phagocytosis activity of OPCs using primary rat OPC cultures. Since innate phagocytosis activity could trigger cell death pathways, we also investigated whether participating in phagocytosis activity may lead to OPC cell death. Our data shows that cultured OPCs phagocytosed myelin‐debris‐rich lysates prepared from rat corpus callosum, without progressing to cell death. In contrast to OPCs, mature oligodendrocytes did not show phagocytotic activity against the bait. OPCs also exhibited phagocytosis towards lysates of rat brain cortex and cell membrane debris from cultured astrocytes, but the percentage of OPCs that phagocytosed beta‐amyloid was much lower than the myelin debris. We then conducted RNA‐seq experiments to examine the transcriptome profile of OPC cultures and found that myelination‐ and migration‐associated genes were downregulated 24 h after phagocytosis. On the other hand, there were a few upregulated genes in OPCs 24 h after phagocytosis. These data confirm that OPCs play a role in debris removal and suggest that OPCs may remain in a quiescent state after phagocytosis. [ABSTRACT FROM AUTHOR]
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- 2023
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35. Preferential Regulation of Γ‐Secretase‐Mediated Cleavage of APP by Ganglioside GM1 Reveals a Potential Therapeutic Target for Alzheimer's Disease.
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Wang, Xiaotong, Zhou, Rui, Sun, Xiaqin, Li, Jun, Wang, Jinxin, Yue, Weihua, Wang, Lifang, Liu, Hesheng, Shi, Yigong, and Zhang, Dai
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ALZHEIMER'S disease , *WESTERN immunoblotting , *MAZE tests , *AMYLOID plaque , *PRESENILINS , *AMYLOID beta-protein precursor , *MOBILE apps - Abstract
A hallmark of Alzheimer's disease (AD) is the senile plaque, which contains β‐amyloid peptides (Aβ). Ganglioside GM1 is the most common brain ganglioside. However, the mechanism of GM1 in modulating Aβ processing is rarely known. Aβ levels are detected by using Immunohistochemistry (IHC) and enzyme‐linked immune‐sorbent assay (ELISA). Cryo‐electron microscopy (Cryo‐EM) is used to determine the structure of γ‐secretase supplemented with GM1. The levels of the cleavage of amyloid precursor protein (APP)/Cadherin/Notch1 are detected using Western blot analysis. Y maze, object translocation, and Barnes maze are performed to evaluate cognitive functions. GM1 leads to conformational change of γ‐secretase structure and specifically accelerates γ‐secretase cleavage of APP without affecting other substrates including Notch1, potentially through its interaction with the N‐terminal fragment of presenilin 1 (PS1). Reduction of GM1 levels decreases amyloid plaque deposition and improves cognitive dysfunction. This study reveals the mechanism of GM1 in Aβ generation and provides the evidence that decreasing GM1 levels represents a potential strategy in AD treatment. These results provide insights into the detailed mechanism of the effect of GM1 on PS1, representing a step toward the characterization of its novel role in the modulation of γ‐secretase activity and the pathogenesis of AD. [ABSTRACT FROM AUTHOR]
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- 2023
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36. Diagnostic performance of fluorescence microscopy with a tetramethylrhodamine isothiocyanate filter in identifying renal amyloidosis.
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Pinedo Pichilingue, Aranza, Thayyil, Abdullah, Dai, Dao‐Fu, and Rastogi, Prerna
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FLUORESCENCE microscopy , *AMYLOIDOSIS , *AMYLOID plaque , *RECEIVER operating characteristic curves , *DELAYED diagnosis - Abstract
Background: Renal amyloidosis (RA) has a worldwide incidence of 5–13 cases per million person‐years and is expected to rise in upcoming years due to growing awareness, plus improvement of diagnostic modalities. Diagnosing RA remains challenging, especially when encountering very small, focal, or early amyloid deposits. Since delays in diagnosis portends poor prognosis, high morbidity, and mortality, it is crucial to evaluate the performance of commonly used diagnostic modalities. This is the first study that presents a full picture of the diagnostic performance of fluorescence microscopy (FM) with a tetramethylrhodamine isothiocyanate (TRITC) filter to diagnose RA in general and stratified by compartments. Materials and methods: A retrospective double‐blind diagnostic accuracy study of FM‐TRITC filter was performed. The presence or absence of amyloid in the vascular, interstitial, and glomerular compartments was established in 316 representative Congo red‐stained core biopsies with an FM‐TRITC filter. This was contrasted with polarized microscopy (PM) showing apple‐green birefringence as the gold standard. Sensitivity, specificity, positive and negative predictive values, likelihood ratios, and the receiver operating characteristic (ROC) curve were obtained using STATA13. Results: The prevalence of RA was 6.01%, comparable with that reported in the literature. Reciprocity with regard to the location and pattern of fluorescence and birefringence between the two diagnostic modalities was seen. The FM‐TRITC filter has a sensitivity of 100%, specificity of 97.64%, and a positive and negative predictive value of 73.08% and 100%, respectively. The positive likelihood ratio was 42.37, and the negative was 0.00. Overall accuracy was 97.78%. The area under the ROC curve was 0.98. The Diagnostic performance of the FM‐TRITC filter stratified by compartments is shown in Table 1. The area under the ROC curve was 0.99, 0.98, and 0.99 for the vascular, interstitial, and glomerular compartment, respectively. All patients with RA (n = 19) were correctly identified; this included one new case, one case with small and focal amyloid, and two early cases with less dense amyloid where birefringence was ambiguous by PM. Discussion: The FM‐TRITC filter is a highly accurate, sensitive, specific, with excellent predictive values, time‐efficient, easy to perform, and suitable to reproduce diagnostic modality for RA. It can accurately rule out RA in all compartments, and in most cases concomitant use of PM should not be indispensable. The diagnosis of vascular, interstitial, and glomerular amyloid deposits can be done using only the FM‐TRITC filter with Congo red‐stained slides. Exceptionally, a few cases of interstitial amyloidosis could be overdiagnosed due to interferences (e.g. artefacts), these cases could be further assessed with a second diagnostic modality if positive fluorescence is seen. Routine use of the FM‐TRITC filter can aid in the diagnosis of early RA, even when the deposits are inconspicuous by PM. [ABSTRACT FROM AUTHOR]
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- 2023
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37. Nodular amyloidosis presenting like a primary scarring alopecia.
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Gulotta, Anthony P., Collins, Joshua M., England, Janessa R., Lew, Jeffrey L., and Lee, Christine M.
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LIQUID chromatography-mass spectrometry , *AMYLOIDOSIS , *SCARS , *BALDNESS , *AMYLOID plaque , *TANDEM mass spectrometry - Abstract
Nodular amyloidosis (NA) is a rare type of primary localized cutaneous amyloidosis in which light chain amyloid deposits in the skin without concurrent systemic involvement. We report a challenging case of NA on the scalp, mimicking primary scarring alopecia, in a relatively young and healthy 36‐year‐old man. In addition to a nonspecific clinical appearance with a broad differential, NA can be a difficult diagnosis because it may require ancillary testing, such as liquid chromatography–tandem mass spectrometry to type the amyloid protein, and hematology–oncology workup to exclude systemic disease. Pathologists can highlight the importance of systemic evaluation in their reports to ensure patients receive appropriate management. [ABSTRACT FROM AUTHOR]
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- 2023
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38. Long Non‐coding RNA H19‐Overexpressing Exosomes Ameliorate UVB‐Induced Photoaging by Upregulating SIRT1Via Sponging miR‐138.
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Gao, Wei, Zhang, Yue, Yuan, Limin, Huang, Fangzhou, and Wang, Yu‐shuai
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LINCRNA , *CIRCULAR RNA , *WRINKLES (Skin) , *EXOSOMES , *AMYLOID plaque , *SIRTUINS , *DNA damage - Abstract
UVB‐induced photoaging is characterized by wrinkle formation, slackness and senile plaques, affecting the health and beauty of human being. Our previous study revealed that exosomes derived from adipose‐derived stem cells (ADSCs) could efficiently alleviate UVB‐induced photodamage. However, the functional ingredients in exosomes were undefined. LncRNA H19, one of the well‐researched lncRNAs in exosomes, exhibits multiple physiological effects. This study aims to demonstrate the photo‐protective role of lncRNA H19 on skin photoaging in UVB‐irradiated human skin fibroblasts cells (HSFs) and Kunming mice. LncRNA H19‐overexpressing exosomes (H19‐Exo) were isolated from the supernatant of ADSCs infected with lncRNA H19‐loaded lentivirus. The results showed that H19‐Exo significantly inhibited MMPs production, DNA damage and ROS generation while enhancing procollagen type I synthesis in UVB‐irradiated HSFs. Meanwhile, H19‐Exo markedly reversed epidermal thickening and collagen degradation in UVB‐irradiated mice. Furthermore, luciferase reporter assays indicated that lncRNA H19 acted as a sponge for miR‐138 expression, and SIRT1 was targeted by miR‐138. Evidence from both in vitro and in vivo studies also revealed that H19‐Exo could enhance SIRT1 expression by knocking down miR‐138. In conclusion, lncRNA H19 served as a therapeutic candidate in treating UVB‐induced skin photoaging by upregulation of SIRT1 via miR‐138. [ABSTRACT FROM AUTHOR]
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- 2023
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39. Age‐related hearing loss and dementia‐related neuropathology: An analysis of the United Kingdom brains for dementia research cohort.
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Katanga, Jessica A., Hamilton, Calum A., Walker, Lauren, Attems, Johannes, and Thomas, Alan J.
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HEARING disorders , *BRAIN research , *NEUROLOGICAL disorders , *ALZHEIMER'S disease , *AMYLOID plaque - Abstract
Age‐related hearing loss frequently precedes or coexists with mild cognitive impairment and dementia. The role specific neuropathologies play in this association, as either a cause or a consequence, is unclear. We therefore aimed to investigate whether specific dementia related neuropathologies were associated with hearing impairment in later life. We analysed data on ante‐mortem hearing impairment with post‐mortem neuropathological data for 442 participants from the Brains for Dementia Research Cohort. Binary logistic regression models were used to estimate the association of hearing impairment with the presence of each dementia‐related neuropathology overall, and with specific staged changes. All analyses adjusted for age and sex, and several sensitivity analyses were conducted to test the robustness of findings. Presence and density of neuritic plaques were associated with higher odds of hearing impairment ante‐mortem (OR = 3.65, 95% CI 1.78–7.46 for frequent density of plaques). Presence of any LB disease was likewise associated with hearing impairment (OR = 2.10, 95% CI 1.27–3.48), but this did not increase with higher cortical pathology (OR = 1.53, 95% CI 0.75–3.11). Nonspecific amyloid deposition, neurofibrillary tangle staging, overall AD neuropathology level, and cerebrovascular disease were not clearly associated with increased risks of hearing impairment. Our results provide some support for an association between dementia‐related neuropathology and hearing loss and suggest that hearing loss may be associated with a high neuritic plaque burden and more common in Lewy body disease. [ABSTRACT FROM AUTHOR]
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- 2023
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- View/download PDF
40. Crosstalk between NLRP3 inflammasome and calpain in Alzheimer's disease.
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Mamsa, Rumaiza, Prabhavalkar, Kedar S., and Bhatt, Lokesh Kumar
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ALZHEIMER'S disease , *CALPAIN , *NLRP3 protein , *INFLAMMASOMES , *AMYLOID plaque , *MEMBRANE potential - Abstract
Amyloid plaques are considered to be the pathological hallmark of Alzheimer's disease (AD). Neuroinflammation further aggravates the pathogenesis of Alzheimer's disease. Calpains and NOD‐like receptor protein‐3 (NLRP3) inflammasomes are involved in the neuroinflammatory pathway and affect the progression of Alzheimer's disease. Hyperactivation of calpains is responsible for the activation of NLRP3 inflammasome, thereby affecting each other's molecular mechanism and causing astrogliosis, microgliosis, and neuronal dysfunction. Further, calpain hyperactivation is also associated with calcium homeostasis that acts as one of the triggers in the activation of NLRP3 inflammasome. Calpain activity is required for the maturation of interleukin‐1β, a key mediator of neuroinflammatory responses. The membrane potential/calcium/calpain/caspase‐1 axis acts as an unconventional regulator of inflammasomes. The complex crosstalk between NLRP3 inflammasome and calpain leads to a series of events. Targeting the molecular mechanism associated with calpain‐NLRP3 inflammasome activation and regulation can be a therapeutic and prophylactic perspective towards Alzheimer's disease. This review discusses calpains and NLRP3 inflammasome crosstalk in the pathogenesis of AD. [ABSTRACT FROM AUTHOR]
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- 2023
- Full Text
- View/download PDF
41. The role of periodontitis‐associated bacteria in Alzheimer's disease: A narrative review.
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Eslami, Saba, Hosseinzadeh Shakib, Nafiseh, Fooladfar, Zahra, Nasrollahian, Sina, Baghaei, Saman, Mosaddad, Seyed Ali, and Motamedifar, Mohammad
- Subjects
ALZHEIMER'S disease ,TAU proteins ,NEUROFIBRILLARY tangles ,AMYLOID plaque ,MICROTUBULE-associated proteins - Abstract
Alzheimer's disease causes memory loss and dementia in older adults through a neurodegenerative mechanism. Despite the pathophysiological clarification of this cognitive disorder, novel molecular and cellular pathways should be identified to determine its exact mechanism. Alzheimer's disease (AD) is pathologically characterized by senile plaques comprising beta‐amyloid and neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau as a microtubule‐associated protein with a key role in the pathogenesis of AD. Periodontitis through inflammatory pathways is a risk factor for deteriorating cognitive impairment in AD patients. Poor oral hygiene coupled with immunocompromised status in older adults causes periodontal diseases and chronic inflammations through an oral bacterial imbalance. Toxic bacterial products, including bacteria themselves, can reach the central nervous system through the bloodstream and evoke inflammatory responses. The present review was conducted to investigate relationships between AD and periodontitis‐involved bacteria as a risk factor. [ABSTRACT FROM AUTHOR]
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- 2023
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- View/download PDF
42. Nanoscale reorganisation of synaptic proteins in Alzheimer's disease.
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Zhu, Wang‐Hui, Yang, Xiao‐Xu, Gou, Xu‐Zhuo, Fu, Shu‐Mei, Chen, Jia‐Hui, Gao, Feng, Shen, Yong, Bi, Dan‐lei, and Tang, Ai‐Hui
- Subjects
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ALZHEIMER'S disease , *NEURAL transmission , *SCAFFOLD proteins , *AMYLOID plaque , *IMAGE reconstruction , *AMPA receptors , *PRESYNAPTIC receptors - Abstract
Aims: Synaptic strength depends strongly on the subsynaptic organisation of presynaptic transmitter release and postsynaptic receptor densities, and their alterations are expected to underlie pathologies. Although synaptic dysfunctions are common pathogenic traits of Alzheimer's disease (AD), it remains unknown whether synaptic protein nano‐organisation is altered in AD. Here, we systematically characterised the alterations in the subsynaptic organisation in cellular and mouse models of AD. Methods: We used immunostaining and super‐resolution stochastic optical reconstruction microscopy imaging to quantitatively examine the synaptic protein nano‐organisation in both Aβ1–42‐treated neuronal cultures and cortical sections from a mouse model of AD, APP23 mice. Results: We found that Aβ1–42‐treatment of cultured hippocampal neurons decreased the synaptic retention of postsynaptic scaffolds and receptors and disrupted their nanoscale alignment to presynaptic transmitter release sites. In cortical sections, we found that while GluA1 receptors in wild‐type mice were organised in subsynaptic nanoclusters with high local densities, receptors in APP23 mice distributed more homogeneously within synapses. This reorganisation, together with the reduced overall receptor density, led to reduced glutamatergic synaptic transmission. Meanwhile, the transsynaptic alignment between presynaptic release‐guiding RIM1/2 and postsynaptic scaffolding protein PSD‐95 was reduced in APP23 mice. Importantly, these reorganisations were progressive with age and were more pronounced in synapses in close vicinity of Aβ plaques with dense cores. Conclusions: Our study revealed a spatiotemporal‐specific reorganisation of synaptic nanostructures in AD and identifies dense‐core amyloid plaques as the major local inductor in APP23 mice. [ABSTRACT FROM AUTHOR]
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- 2023
- Full Text
- View/download PDF
43. Therapeutic potential of aromatic plant extracts in Alzheimer's disease: Comprehensive review of their underlying mechanisms.
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Ma, Yue, Li, Yingming, Yin, Run, Guo, Peixin, Lei, Nai, Li, Gang, Xiong, Lei, and Xie, Yuhuan
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PLANT extracts , *ALZHEIMER'S disease , *AROMATIC plants , *MEDICAL botany , *INHALATION administration , *AMYLOID plaque - Abstract
Aims: The aim of this review is to outline recent advancements in the application and mechanistic studies of aromatic plant extracts in Alzhermer's disease (AD) to demonstrate their value in the management of this disease. Background: AD is a neurodegenerative disease with a complex pathogenesis characterized by severe cognitive impairment. Currently, there are very few drugs available for the treatment of AD, and treatments are primarily focused on symptom relief. Aromatherapy is a traditional complementary alternative therapy that focuses on the prevention and treatment of the disease through the inhalation or transdermal administration of aromatic plant extracts. Over the past few years, studies on the use of aromatic plant extracts for the treatment of AD have been increasing and have demonstrated a definitive therapeutic effect. Methods: We systematically summarized in vitro, in vivo, and clinical studies focusing on the potential use of aromatic plant extracts in the treatment of AD in PubMed, ScienceDirect, Google Scholar, and the Chinese National Knowledge Infrastructure from 2000 to 2022. Results: Our literature survey indicates that aromatic plant extracts exert anti‐AD effects by modulating pathological changes through anti‐amyloid, anti‐tau phosphorylation, anti‐cholinesterase, anti‐inflammation, and anti‐oxidative stress mechanisms (Figure 1). Conclusion: This review provides a future strategy for the research of novel anti‐AD drugs from aromatic plant extracts. [ABSTRACT FROM AUTHOR]
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- 2023
- Full Text
- View/download PDF
44. Proteomics of the astrocyte secretome reveals changes in their response to soluble oligomeric Aβ.
- Author
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Matafora, Vittoria, Gorb, Alena, Yang, Fangjia, Noble, Wendy, Bachi, Angela, Perez‐Nievas, Beatriz Gomez, and Jimenez‐Sanchez, Maria
- Subjects
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AMYLOID beta-protein precursor , *EXTRACELLULAR matrix proteins , *CEREBROSPINAL fluid examination , *ALZHEIMER'S disease , *AMYLOID plaque , *CEREBROSPINAL fluid , *RHINORRHEA , *PROTEOMICS - Abstract
Astrocytes associate with amyloid plaques in Alzheimer's disease (AD). Astrocytes react to changes in the brain environment, including increasing concentrations of amyloid‐β (Aβ). However, the precise response of astrocytes to soluble small Aβ oligomers at concentrations similar to those present in the human brain has not been addressed. In this study, we exposed astrocytes to media from neurons that express the human amyloid precursor protein (APP) transgene with the double Swedish mutation (APPSwe), and which contains APP‐derived fragments, including soluble human Aβ oligomers. We then used proteomics to investigate changes in the astrocyte secretome. Our data show dysregulated secretion of astrocytic proteins involved in the extracellular matrix and cytoskeletal organization and increase secretion of proteins involved in oxidative stress responses and those with chaperone activity. Several of these proteins have been identified in previous transcriptomic and proteomic studies using brain tissue from human AD and cerebrospinal fluid (CSF). Our work highlights the relevance of studying astrocyte secretion to understand the brain response to AD pathology and the potential use of these proteins as biomarkers for the disease. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
45. Could routine vaccinations prevent dementia?
- Author
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Poynton‐Smith, Emma, Orrell, Martin, Morley, John E., and Scherrer, Jeffrey F.
- Subjects
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INFLAMMATION prevention , *DEMENTIA risk factors , *DEMENTIA prevention , *HYPERTENSION , *OBESITY , *INFLUENZA vaccines , *IMMUNIZATION , *ALCOHOLISM , *DPT vaccines , *INFLAMMATION , *SELF-evaluation , *IMMUNE system , *AMYLOID plaque , *DIABETES , *PARADIGMS (Social sciences) , *RISK assessment , *CONCEPTUAL structures , *DEMENTIA , *AGING , *MENTAL depression , *BCG vaccines , *HERPES zoster vaccines , *SMOKING , *CAUSALITY (Physics) - Abstract
An editorial is presented which explores the potential link between routine vaccinations (e.g., influenza vaccines) and reduced risk of dementia, based on emerging evidence of the role of the immune system and inflammation in dementia pathogenesis and various studies suggesting a protective link between some routinely used vaccines and dementia. The authors use the Bradford-Hill criteria, an epidemiological approach.
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- 2023
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46. Depletion of ESCRT ameliorates APP‐induced AD‐like symptoms in Drosophila.
- Author
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Zhuang, Luming, Li, Chenglin, Peng, Fei, Xue, Elleen, Li, Wenzhe, Sun, Xinyue, Chen, Ping, Zhou, Qian, and Xue, Lei
- Subjects
- *
AMYLOID beta-protein precursor , *AMPA receptors , *DROSOPHILA , *DOPAMINE receptors , *ALZHEIMER'S disease , *DOPAMINERGIC neurons , *AMYLOID plaque - Abstract
The amyloid‐β (Aβ) peptide, produced from amyloid precursor protein (APP) by β and γ‐secretases, has been implicated in the etiology of Alzheimer's disease (AD). However, the precise intracellular trafficking pathway of APP and its subcellular locations to produce Aβ have remained unclear. To address these issues, we established fly AD models that recapitulated multiple AD‐like symptoms by expressing human APP in the Drosophila nerve system. The ESCRT (endosomal sorting complexes required for transport) machinery regulates the sorting and trafficking of endocytosed proteins, yet its role in AD pathogenesis has not been explored in vivo. We found that knockdown of distinct ESCRT components ameliorated APP‐induced morphological and behavioral defects, including impaired wing expansion, eye degeneration, dopamine neuron loss, locomotor disability, lifespan shortening, and cognitive deficits. Mechanistically, we showed that impaired ESCRT impeded APP's intracellular transportation from early endosomes to late endosomes, resulting in reduced Aβ production and amyloid deposit load. These data suggest that APP undergoes ESCRT‐mediated endocytic trafficking, and Aβ is generated mainly in late endosomes. Our data provide the first in vivo evidence to support a physiological role of ESCRT in AD pathogenesis, suggesting that interfering with ESCRT machinery might be an alternative therapeutic strategy for AD. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
47. Suvorexant Acutely Decreases Tau Phosphorylation and Aβ in the Human CNS.
- Author
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Lucey, Brendan P., Liu, Haiyan, Toedebusch, Cristina D., Freund, David, Redrick, Tiara, Chahin, Samir L., Mawuenyega, Kwasi G., Bollinger, James G., Ovod, Vitaliy, Barthélemy, Nicolas R., and Bateman, Randall J.
- Subjects
- *
TAU proteins , *LIQUID chromatography-mass spectrometry , *ALZHEIMER'S disease , *NEUROFIBRILLARY tangles , *AMYLOID plaque , *FLUID intelligence - Abstract
Objective: In Alzheimer's disease, hyperphosphorylated tau is associated with formation of insoluble paired helical filaments that aggregate as neurofibrillary tau tangles and are associated with neuronal loss and cognitive symptoms. Dual orexin receptor antagonists decrease soluble amyloid‐β levels and amyloid plaques in mouse models overexpressing amyloid‐β, but have not been reported to affect tau phosphorylation. In this randomized controlled trial, we tested the acute effect of suvorexant, a dual orexin receptor antagonist, on amyloid‐β, tau, and phospho‐tau. Methods: Thirty‐eight cognitively unimpaired participants aged 45 to 65 years were randomized to placebo (N = 13), suvorexant 10 mg (N = 13), and suvorexant 20 mg (N = 12). Six milliliters of cerebrospinal fluid were collected via an indwelling lumbar catheter every 2 hours for 36 hours starting at 20:00. Participants received placebo or suvorexant at 21:00. All samples were processed and measured for multiple forms of amyloid‐β, tau, and phospho‐tau via immunoprecipitation and liquid chromatography‐mass spectrometry. Results: The ratio of phosphorylated‐tau‐threonine‐181 to unphosphorylated‐tau‐threonine‐181, a measure of phosphorylation at this tau phosphosite, decreased ~10% to 15% in participants treated with suvorexant 20 mg compared to placebo. However, phosphorylation at tau‐serine‐202 and tau‐threonine‐217 were not decreased by suvorexant. Suvorexant decreased amyloid‐β ~10% to 20% compared to placebo starting 5 hours after drug administration. Interpretation: In this study, suvorexant acutely decreased tau phosphorylation and amyloid‐β concentrations in the central nervous system. Suvorexant is approved by the US Food and Drug Administration to treatment insomnia and may have potential as a repurposed drug for the prevention of Alzheimer's disease, however, future studies with chronic treatment are needed. ANN NEUROL 2023;94:27–40 [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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48. Amyloid beta plaque accumulation with longitudinal [18F]AZD4694 PET.
- Author
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Therriault, Joseph, Lussier, Firoza Z., Tissot, Cécile, Chamoun, Mira, Stevenson, Jenna, Rahmouni, Nesrine, Pallen, Vanessa, Bezgin, Gleb, Servaes, Stijn, Kunach, Peter, Wang, Yi‐Ting, Fernandez‐Arias, Jaime, Vermeiren, Marie, Pascoal, Tharick A., Massarweh, Gassan, Vitali, Paolo, Soucy, Jean‐Paul, Saha‐Chaudhuri, Paramita, Gauthie, Serge, and Rosa‐Neto, Pedro
- Subjects
AMYLOID plaque ,POSITRON emission tomography ,MILD cognitive impairment ,OLDER people ,CLINICAL trials - Abstract
Introduction: [18F]AZD4694 is an amyloid beta (Aβ) imaging agent used in several observational studies and clinical trials. However, no studies have yet published data on longitudinal Aβ accumulation measured with [18F]AZD4694. Methods: We assessed 146 individuals who were evaluated with [18F]AZD4694 at baseline and 2‐year follow‐up. We calculated annual rates of [18F]AZD4694 change for clinically defined and biomarker‐defined groups Results: Cognitively unimpaired (CU) older adults displayed subtle [18F]AZD4694 standardized uptake value ratio (SUVR) accumulation over the follow‐up period. In contrast, Aβ positive CU older adults displayed higher annual [18F]AZD4694 SUVR increases. [18F]AZD4694 SUVR accumulation in Aβ positive mild cognitive impairment (MCI) and dementia was modest across the neocortex Discussion: Larger increases in [18F]AZD4694 SUVR were observed in CU individuals who had abnormal amyloid positron emission tomography levels at baseline. [18F]AZD4694 can be used to monitor Aβ levels in therapeutic trials as well as clinical settings, particularly prior to initiating anti‐amyloid therapies. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
49. Ethnobotanical significance of medicinal plants: Beta‐amyloid and tau aggregation inhibitors against Alzheimer's disease.
- Author
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Ganapathy, A. Anand, Haripriya, Vijayakumari M., Acharya, Niyati, Somappa, Sasidhar B., and Kumaran, Alaganandam
- Subjects
TAU proteins ,ALZHEIMER'S disease ,MEDICINAL plants ,NEUROFIBRILLARY tangles ,AMYLOID plaque ,PLANT products - Abstract
Among the various neurodegenerative disorders, Alzheimer's disease (AD) is identified as one of primary causes of dementia in the elderly, which progresses slowly leading to cognitive decline and ability to function independently. Although various pathological mechanisms have been proposed, the exact mechanism is not yet elucidated. Numerous processes such as old age, mitochondrial dysfunction, and genetics lead to the aggregation of beta‐amyloid (Aβ) as amyloid plaques and tau proteins as neurofibrillary tangles in the neurons leading to their death and destruction, finally leading to AD. The current treatment measures can only temporarily improve the symptoms, slowing cognitive decline without any effect on AD pathology for better therapeutic effect. Furthermore, the high failure rates of a number of drugs during clinical trials due to their side effects has led the researchers to focus on alternative sources for drug development. As natural ingredients were considered the primary line of treatment in the olden days, and as several medicinal plant products are also proven as effective AD targets, it will be wise to investigate those with significant ethnobotanical value as potential neuroprotectives, nootropics or memory boosters. Throughout the study, propanoids, glycosides, iridoids, carotenoids and flavonoids that show potential anti‐inflammatory, antioxidant, and anti‐cholinesterase were also found to be inhibitors of Aβ and tau aggregation, where Saikosaponin C, Fisetin, and Morin can act as dual inhibitors. The review provides an insight in the need for proper and complete scientific evaluation of these ethnobotanically useful medicinal plants to be identified as potential leads in AD therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
50. Donanemab Population Pharmacokinetics, Amyloid Plaque Reduction, and Safety in Participants with Alzheimer's Disease.
- Author
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Gueorguieva, Ivelina, Willis, Brian A., Chua, Laiyi, Chow, Kay, Ernest, C. Steven, Shcherbinin, Sergey, Ardayfio, Paul, Mullins, Garrett R., and Sims, John R.
- Subjects
AMYLOID plaque ,ALZHEIMER'S disease ,MILD cognitive impairment ,PHARMACOKINETICS ,ANTIBODY titer ,NEUROFIBRILLARY tangles ,EXUDATES & transudates - Abstract
Donanemab is an amyloid‐targeting therapy that resulted in robust amyloid plaque reduction and slowed Alzheimer's disease (AD) progression compared with placebo in the phase II TRAILBLAZER‐ALZ study (NCT03367403). The objectives of the current analyses are to characterize (i) the population pharmacokinetics of donanemab, (ii) the relationship between donanemab exposure and amyloid plaque reduction (response), and (iii) the relationship between donanemab exposure and amyloid‐related imaging abnormalities with edema or effusions (ARIA‐E). Model development included data from participants with mild cognitive impairment or mild to moderate dementia due to AD from the phase Ib study on donanemab (NCT02624778) and participants with early symptomatic AD from the TRAILBLAZER‐ALZ study. The analysis showed donanemab has a terminal elimination half‐life of 11.8 days. Body weight and antidrug antibody titer impact donanemab exposure but not the pharmacodynamic response. Maintaining a donanemab serum concentration above 4.43 μg/mL (95% confidence interval: 0.956, 10.4) is associated with amyloid plaque reduction. The time to achieve amyloid plaque clearance (amyloid plaque level < 24.1 Centiloids) varied depending on the baseline amyloid level, where higher baseline levels were associated with fewer participants achieving amyloid clearance. The majority of participants achieved amyloid clearance by 52 weeks on treatment. Apolipoprotein ε4 carriers, irrespective of donanemab serum exposure, were 4 times more likely than noncarriers to have an ARIA‐E event by 24 weeks. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
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