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[18F]Flortaucipir is an FDA-approved tau-PET tracer that is increasingly utilized in clinical settings for the diagnosis of Alzheimer's disease. Still, a large-scale comparison of the in vivo PET uptake to quantitative post-mortem tau pathology and to other co-pathologies is lacking. Here, we examined the correlation between in vivo [18F]flortaucipir PET uptake and quantitative post-mortem tau pathology in corresponding brain regions from the AVID A16 end-of-life study (n = 63). All participants underwent [18F]flortaucipir PET scans prior to death, followed by a detailed post-mortem neuropathological examination using AT8 (tau) immunohistochemistry. Correlations between [18F]flortaucipir standardized uptake value ratios (SUVRs) and AT8 immunohistochemistry were assessed across 18 regions-of-interest (ROIs). To assess [18F]flortaucipir specificity and level of detection for tau pathology, correlations between [18F]flortaucipir SUVR and neuritic plaque score and TDP-43 stage were also computed and retention was further assessed in individuals with possible primary age-related tauopathy (PART), defined as Thal phase ≤ 2 and Braak stage I–IV. We found modest-to-strong correlations between in vivo [18F]flortaucipir SUVR and post-mortem tau pathology density in corresponding brain regions in all neocortical regions analyzed (rho-range = 0.61–0.79, p < 0.0001 for all). The detection threshold of [18F]flortaucipir PET was determined to be 0.85% of surface area affected by tau pathology in a temporal meta-ROI, and 0.15% in a larger cortical meta-ROI. No significant associations were found between [18F]flortaucipir SUVRs and post-mortem tau pathology in individuals with possible PART. Further, there was no correlation observed between [18F]flortaucipir and level of amyloid-β neuritic plaque load (rho-range = – 0.16–0.12; p = 0.48–0.61) or TDP-43 stage (rho-range = – 0.10 to – 0.30; p = 0.18–0.65). In conclusion, our in vivo vs post-mortem study shows that the in vivo [18F]flortaucipir PET signal primarily reflects tau pathology, also at relatively low densities of tau proteinopathy, and does not bind substantially to tau neurites in neuritic plaques or in individuals with PART. [ABSTRACT FROM AUTHOR]

Objective: Rare disease Background: Amyloidosis results in fibrillar sheets of beta-pleated amorphous congophilic protein deposition in the extracellular space. Breast amyloidosis is a rare entity, with the first case reported in 1973 and only 2 major case series published since. These deposits can have local or systemic manifestations and typically present unilaterally, although bilateral involvement has been described. Some reported cases of amyloidosis have been linked to breast cancer. Case Report: The patient was a 60-year-old woman who presented to the breast surgery clinic for evaluation after imageguided biopsy of a right breast lesion. Core needle biopsy under stereotactic guidance demonstrated pathology consistent with nodular deposition of amyloid, associated with calcifications. Microscopic examination revealed extracellular deposition of acellular eosinophilic material in fat, stoma, and blood vessels. Congo red special stain was positive. Amyloid with Congo red special stain showed apple green birefringence under polarized light. Surgical excision under needle localization was performed, with the final surgical pathology report confirming amyloid deposits. Conclusions: Breast amyloidosis can have calcium affinity, create a foreign body-like reaction with giant cell infiltration, and distribute through periductal, perivascular, or intralobar patterns. Some factors that can contribute to an increased risk or are associated with breast amyloidosis are predisposing clinical conditions, including autoimmune disease, various breast cancers, and B-cell lymphomas. Amyloidosis of the breast should be treated either as primary or secondary, based on etiology. Further studies need to be conducted on whether there are specific genetic markers that predispose populations to the development of amyloidosis of the breast. [ABSTRACT FROM AUTHOR]

Periodontitis is a chronic inflammatory disease driven by dysbiosis in subgingival microbial communities leading to increased abundance of a limited number of pathobionts, including Porphyromonas gingivalis and Treponema denticola. Oral health, particularly periodontitis, is a modifiable risk factor for Alzheimer disease (AD) pathogenesis, with components of both these bacteria identified in postmortem brains of persons with AD. Repeated oral inoculation of mice with P. gingivalis results in brain infiltration of bacterial products, increased inflammation, and induction of AD-like biomarkers. P. gingivalis displays synergistic virulence with T. denticola during periodontitis. The aim of the current study was to determine the ability of P. gingivalis and T. denticola , grown in physiologically relevant conditions, individually and in combination, to induce AD-like pathology following chronic oral inoculation of female mice over 12 weeks. P. gingivalis alone significantly increased all 7 brain pathologies examined: neuronal damage, activation of astrocytes and microglia, expression of inflammatory cytokines interleukin 1β (IL-1β) and interleukin 6 and production of amyloid-β plaques and hyperphosphorylated tau, in the hippocampus, cortex and midbrain, compared to control mice. T. denticola alone significantly increased neuronal damage, activation of astrocytes and microglia, and expression of IL-1β, in the hippocampus, cortex and midbrain, compared to control mice. Coinoculation of P. gingivalis with T. denticola significantly increased activation of astrocytes and microglia in the hippocampus, cortex and midbrain, and increased production of hyperphosphorylated tau and IL-1β in the hippocampus only. The host brain response elicited by oral coinoculation was less than that elicited by each bacterium, suggesting coinoculation was less pathogenic. [ABSTRACT FROM AUTHOR]

Alzheimer's Disease (AD) is a chronic neurodegenerative disorder constituting the most common form of dementia (60%-70% of cases). Although AD presents majorly a neurodegenerative pathology, recent clinical evidence highlights myelin impairment as a key factor in disease pathogenesis. The lack of preventive or restorative treatment is emphasizing the need to develop novel therapeutic approaches targeting to the causes of the disease. Recent studies in animals and patients have highlighted the loss of myelination of the neuronal axons as an extremely aggravating factor in AD, in addition to the formation of amyloid plaques and neurofibrillary tangles that are to date themain pathological hallmarks of the disease. Myelin breakdown represents an early stage event in AD. However, it is still unclear whether myelin loss is attributed only to exogenous factors like inflammatory processes of the tissue or to impaired oligodendrogenesis as well. Neurotrophic factors are well established protective molecules under many pathological conditions of the neural tissue, contributing also to proper myelination. Due to their inability to be used as drugs, many research efforts are focused on substituting neurotrophic activity with small molecules. Our research team has recently developed novel micromolecular synthetic neurotrophin mimetics (MNTs), selectively acting on neurotrophin receptors, and thus offering a unique opportunity for innovative therapies against neurodegenerative diseases. These small sized, lipophilic molecules address the underlying biological effect of these diseases (neuroprotective action), but also they exert significant neurogenic actions inducing neuronal replacement of the disease areas. One of the significant neurotrophinmolecules in the Central Nervous System is Brain-Derived-Neurotrophin-Factor (BDNF). BDNF is a neurotrophin that not only supports neuroprotection and adult neurogenesis, but also mediates pro-myelinating effects in the CNS. BDNF binds with high-affinity on the TrkB neurotrophin receptor and enhances myelination by increasing the density of oligodendrocyte progenitor cells (OPCs) and playing an important role in CNS myelination. Conclusively, in the present review, we discuss the myelin pathophysiology in Alzheimer's Diseases, as well as the role of neurotrophins, and specifically BDNF, in myelin maintenance and restoration, revealing its valuable therapeutic potential against AD. [ABSTRACT FROM AUTHOR]

Objective: Tinnitus may be associated with various brain changes. However, the degenerative changes in patients with tinnitus have not been extensively investigated. We aimed to evaluate degenerative, structural, and functional brain changes in patients with mild cognitive impairment (MCI) who also suffer from tinnitus. Materials and methods: This study included participants aged 60 to 80 years with MCI and a hearing level better than 40 dB. The participants were classified into two groups: MCI with tinnitus (MCI-T) and MCI without tinnitus (MCI-NT). All patients underwent Tinnitus Handicap Inventory (THI), 3 T brain MRI, F18-florapronol PET, and F18-FDG PET. Results: The MCI-T group exhibited higher ß-amyloid deposition in the superior temporal gyrus, temporal pole, and middle temporal gyrus compared to the MCI-NT group (p < 0.05 for all). Additionally, the MCI-T group showed increased metabolism in the inferior frontal gyrus, insula, and anterior cingulate cortex (ACC) (p < 0.005 for all). The THI score was strongly correlated with increased volume in the insula, ACC, superior frontal gyrus, supplementary motor area, white matter near the hippocampus, and precentral gyrus (p < 0.05 for all). Moreover, the MCI-T group demonstrated higher metabolic activity in the default mode network (DMN) and lower activity in the executive control network (ECN) (p < 0.05 for all). In the MCI-T group, the posterior DMN was positively correlated with the visual network and negatively with the ECN, whereas in the MCI-NT group, it correlated positively with the ECN. Conclusion: The MCI-T group exhibited greater ß-amyloid accumulation in the auditory cortex and more extensive changes across various brain networks compared with the MCI-NT group, potentially leading to diverse clinical symptoms such as dementia with semantic deficits or depression. Tinnitus in MCI patients may serve as a biomarker for degenerative changes in the temporal lobe and alterations in brain network dynamics. [ABSTRACT FROM AUTHOR]

Background: Amyloid toxicity and glucose metabolic disorders are key pathological features during the progression of Alzheimer's disease (AD). While the hypothalamus plays a crucial role in regulating systemic energy balance, the distribution of amyloid plaques in the preoptic, anterior, tuberal, and mammillary regions of the hypothalamus in AD mice, particularly across both sexes, remains largely unclear. Our ongoing research aims to explore hypothalamic neuropathology and glucose metabolic disturbances in a well-described APP/PS1 mouse model of AD. Results: Immunocytochemical staining revealed that Old-AD-Female mice exhibited a greater hypothalamic Amyloid β (Aβ) burden than their Old-AD-Male counterparts, with the mammillary bodies showing the most severe accumulation. Analysis of ionized calcium binding adaptor molecule 1 (IBA1) immunoreactivity and Iba1 mRNA indicated differential microgliosis based on sex, while tanycytic territory and ZO-1 tight junction protein expression remained stable in AD mice. Moreover, sex-specific peripheral glucose metabolic parameters (random and fasting blood glucose) seemed to be exacerbated by age. Old AD mice of both sexes exhibited limited hypothalamic activation (c-Fos + cells) in response to blood glucose fluctuations. Hypothalamic Glut 1 expression decreased in young but increased in old female AD mice compared with age-matched male AD mice. Pearson correlation analysis further supported a negative correlation between hypothalamic Aβ load and random blood glucose in old AD groups of both genders, shedding light on the mechanisms underlying this amyloidosis mouse model. Conclusion: Aged APP/PS1 mice exhibit sex-specific hypothalamic neuropathology and differential glucose metabolism, highlighting distinct pathological mechanisms within each gender. [ABSTRACT FROM AUTHOR]

The aggregation of amyloid β (Aβ) peptides is a significant hallmark of Alzheimer's disease (AD), and the detection of Aβ aggregates and the inhibition of their formation are important for the diagnosis and treatment of AD, respectively. Herein, we report a series of benzothiazole-based Ir(III) complexes HN-1 to HN-8 that exhibit appreciable inhibition of Aβ aggregation in vitro and in living cells. These Ir(III) complexes can induce a significant fluorescence increase when binding to Aβ fibrils and Aβ oligomers, while their measured log D values suggest these compounds could have enhanced blood--brain barrier (BBB) permeability. In vivo studies show that HN-1, HN-2, HN-3, and HN-8 successfully penetrate the BBB and stain the amyloid plaques in AD mouse brains after a 10-day treatment, suggesting that these Ir(III) complexes could act as lead compounds for AD therapeutic and diagnostic agent development. [ABSTRACT FROM AUTHOR]

Autophagy, the major lysosomal pathway for degrading damaged or obsolete constituents, protects neurons by eliminating toxic organelles and peptides, restoring nutrient and energy homeostasis, and inhibiting apoptosis. These functions are especially vital in neurons, which are postmitotic and must survive for many decades while confronting mounting challenges of cell aging. Autophagy failure, especially related to the declining lysosomal ("phagy") functions, heightens the neuron's vulnerability to genetic and environmental factors underlying Alzheimer's disease (AD) and other late-age onset neurodegenerative diseases. Components of the global autophagy–lysosomal pathway and the closely integrated endolysosomal system are increasingly implicated as primary targets of these disorders. In AD, an imbalance between heightened autophagy induction and diminished lysosomal function in highly vulnerable pyramidal neuron populations yields an intracellular lysosomal build-up of undegraded substrates, including APP-βCTF, an inhibitor of lysosomal acidification, and membrane-damaging Aβ peptide. In the most compromised of these neurons, β-amyloid accumulates intraneuronally in plaque-like aggregates that become extracellular senile plaques when these neurons die, reflecting an "inside-out" origin of amyloid plaques seen in human AD brain and in mouse models of AD pathology. In this review, the author describes the importance of lysosomal-dependent neuronal cell death in AD associated with uniquely extreme autophagy pathology (PANTHOS) which is described as triggered by lysosomal membrane permeability during the earliest "intraneuronal" stage of AD. Effectors of other cell death cascades, notably calcium-activated calpains and protein kinases, contribute to lysosomal injury that induces leakage of cathepsins and activation of additional death cascades. Subsequent events in AD, such as microglial invasion and neuroinflammation, induce further cytotoxicity. In major neurodegenerative disease models, neuronal death and ensuing neuropathologies are substantially remediable by reversing underlying primary lysosomal deficits, thus implicating lysosomal failure and autophagy dysfunction as primary triggers of lysosomal-dependent cell death and AD pathogenesis and as promising therapeutic targets. [ABSTRACT FROM AUTHOR]

The generation of new neurons at the hippocampal neurogenic niche, known as adult hippocampal neurogenesis (AHN), and its impairment, have been implicated in Alzheimer's disease (AD). MicroRNA-132 (miR-132), the most consistently downregulated microRNA (miRNA) in AD, was recently identified as a potent regulator of AHN, exerting multilayered proneurogenic effects in adult neural stem cells (NSCs) and their progeny. Supplementing miR-132 in AD mouse brain restores AHN and relevant memory deficits, yet the exact mechanisms involved are still unknown. Here, we identify NACC2 as a novel miR-132 target implicated in both AHN and AD. miR-132 deficiency in mouse hippocampus induces Nacc2 expression and inflammatory signaling in adult NSCs. We show that miR-132-dependent regulation of NACC2 is involved in the initial stages of human NSC differentiation towards astrocytes and neurons. Later, NACC2 function in astrocytic maturation becomes uncoupled from miR-132. We demonstrate that NACC2 is present in reactive astrocytes surrounding amyloid plaques in mouse and human AD hippocampus, and that there is an anticorrelation between miR-132 and NACC2 levels in AD and upon induction of inflammation. Unraveling the molecular mechanisms by which miR-132 regulates neurogenesis and cellular reactivity in AD, will provide valuable insights towards its possible application as a therapeutic target. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a complex neurodegenerative disease that affects elderly individuals, characterized by senile plaques formed by extracellular amyloid beta (Aβ). Autophagy dysfunction is a manifestation of protein homeostasis imbalance in patients with AD, but its relationship with Aβ remains unclear. Here, we showed that in Aβ transgenic Caenorhabditis elegans, Aβ activated the TOR pathway and reduced the nuclear entry of HLH-30, leading to autophagy dysfunction characterized by autophagosome accumulation. Then, utilizing RNA-seq, we investigated the regulatory mechanisms by which HLH-30 modulates autophagy in C. elegans. We found that HLH-30 elevated the transcript levels of v-ATPase and cathepsin, thus enhancing lysosomal activity. This led to an increase in autophagic flux, facilitating more pronounced degradation of Aβ. Moreover, HLH-30 reduced the level of ROS induction by Aβ and enhanced the antioxidant stress capacity of the worms through the gsto-1 gene. Additionally, we identified two HLH-30/TFEB activators, saikosaponin B2 and hypericin, that improved autophagic flux, thereby enhancing protein homeostasis in C. elegans. Overall, our findings suggested that HLH-30/TFEB plays a key role in modulating autophagy and can be considered a promising drug target for AD treatments. [ABSTRACT FROM AUTHOR]

Systemic amyloidosis involves the deposition of misfolded proteins in organs/tissues, leading to progressive organ dysfunction and failure. Congo red is the gold-standard chemical stain for visualizing amyloid deposits in tissue, showing birefringence under polarization microscopy. However, Congo red staining is tedious and costly to perform, and prone to false diagnoses due to variations in amyloid amount, staining quality and manual examination of tissue under a polarization microscope. We report virtual birefringence imaging and virtual Congo red staining of label-free human tissue to show that a single neural network can transform autofluorescence images of label-free tissue into brightfield and polarized microscopy images, matching their histochemically stained versions. Blind testing with quantitative metrics and pathologist evaluations on cardiac tissue showed that our virtually stained polarization and brightfield images highlight amyloid patterns in a consistent manner, mitigating challenges due to variations in chemical staining quality and manual imaging processes in the clinical workflow. Detecting amyloid deposits in tissue with Congo red can be limited by several factors, which can potentially lead to false diagnoses. Here, the authors use virtual birefringence imaging and virtual Congo red staining using autofluorescence of label-free human tissue, highlighting amyloid deposits in a consistent manner. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) represents a devastating form of neurodegeneration, hallmarked by a relentless erosion of memory and cognitive faculties. One key player in this complex pathology is hydrogen sulfide (H2S), a gaseous neurotransmitter that is highly concentrated in the brain. Its fluctuating levels have been compellingly linked to the onset and progression of AD. Despite the availability of numerous fluorescent probes for detecting H2S, targeted imaging of this neurotransmitter within AD models remains underexplored. To bridge this gap, we have engineered an innovative near-infrared (NIR) "turn-on" fluorescent probe, designated as probe 1. Crafted around a dicyanoisophorone scaffold, the probe incorporates a strategic methoxy modification to facilitate a bathochromic spectral shift. Impressively, upon binding with H2S, probe 1 exhibited a robust 46-fold enhancement in fluorescence at a wavelength of 680 nm. We successfully deployed this probe to visualize both exogenous and endogenous H2S in living cells and zebrafish. Further, our pathogenic investigations have corroborated that diminished H2S levels are intricately linked to an escalation in amyloid plaque formation. Most crucially, we employed probe 1 to capture real-time images of H2S concentrations within the hippocampal tissue of AD mouse models. This revealed a significant depletion in H2S levels, thereby underscoring the probe's immense potential as an effective tool for the diagnosis and prevention of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized pathologically by extracellular deposition of β-amyloid (Aβ) into senile plaques and intracellular accumulation of hyperphosphorylated tau (pTau) as neurofibrillary tangles. Clinically, AD patients show memory deterioration with varying cognitive dysfunctions. The exact molecular mechanisms underlying AD are still not fully understood, and there are no efficient drugs to stop or reverse the disease progression. In this review, we first provide an update on how the risk factors, including APOE variants, infections and inflammation, contribute to AD; how Aβ and tau become abnormally accumulated and how this accumulation plays a role in AD neurodegeneration. Then we summarize the commonly used experimental models, diagnostic and prediction strategies, and advances in periphery biomarkers from high-risk populations for AD. Finally, we introduce current status of development of disease-modifying drugs, including the newly officially approved Aβ vaccines, as well as novel and promising strategies to target the abnormal pTau. Together, this paper was aimed to update AD research progress from fundamental mechanisms to the clinical diagnosis and therapies. [ABSTRACT FROM AUTHOR]

The amyloid cascade hypothesis postulates that extracellular deposits of amyloid β (Aβ) are the primary and initial cause leading to the full development of Alzheimer's disease (AD) with intracellular neurofibrillary tangles; however, the details of this mechanism have not been fully described until now. Our preliminary data, coming from our day-to-day neuropathology practice, show that the primary location of the hyperphosphorylated tau protein is in the vicinity of the cell membrane of dystrophic neurites. This observation inspired us to formulate a hypothesis that presumes an interaction between low-density lipoprotein receptor-related protein 1 (LRP1) and fibrillar aggregates of, particularly, Aβ42 anchored at the periphery of neuritic plaques, making internalization of the LRP1-Aβ42 complex infeasible and, thus, causing membrane dysfunction, leading to the tauopathy characterized by intracellular accumulation and hyperphosphorylation of the tau protein. Understanding AD as a membrane dysfunction tauopathy may draw attention to new treatment approaches not only targeting Aβ42 production but also, perhaps paradoxically, preventing the formation of LRP1-Aβ42. [ABSTRACT FROM AUTHOR]

Amyloid-beta peptide (Aβ) is a neurotoxic constituent of senile plaques in the brains of Alzheimer's disease (AD) patients. The detailed mechanisms by which protein kinase C-delta (PKCδ) contributes to Aβ toxicity is not yet entirely understood. Using fully differentiated primary rat cortical neurons, we found that inhibition of Aβ25-35-induced PKCδ increased cell viability with restoration of neuronal morphology. Using cyclin D1, proliferating cell nuclear antigen (PCNA), and histone H3 phosphorylated at Ser-10 (p-Histone H3) as the respective markers for the G1-, S-, and G2/M-phases, PKCδ inhibition mitigated cell cycle reentry (CCR) and subsequent caspase-3 cleavage induced by both Aβ25-35 and Aβ1-42 in the post-mitotic cortical neurons. Upstream of PKCδ, signal transducers and activators of transcription (STAT)-3 mediated PKCδ induction, CCR, and caspase-3 cleavage upon Aβ exposure. Downstream of PKCδ, aberrant neuronal CCR was triggered by overactivating cyclin-dependent kinase-5 (CDK5) via calpain2-dependent p35 cleavage into p25. Finally, PKCδ and CDK5 also contributed to Aβ25-35 induction of p53-upregulated modulator of apoptosis (PUMA) in cortical neurons. Together, we demonstrated that, in the post-mitotic neurons exposed to Aβs, STAT3-dependent PKCδ expression triggers calpain2-mediated p35 cleavage into p25 to overactivate CDK5, thus leading to aberrant CCR, PUMA induction, caspase-3 cleavage, and ultimately apoptosis. [ABSTRACT FROM AUTHOR]

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]

Background: While Alzheimer's disease (AD) has been extensively studied with a focus on cognitive networks, visual network dysfunction has received less attention despite compelling evidence of its significance in AD patients and mouse models. We recently reported c-Fos and synaptic dysregulation in the primary visual cortex of a pre-amyloid plaque AD-model. Objective: We test whether c-Fos expression and presynaptic density/dynamics differ in cortical and subcortical visual areas in an AD-model. We also examine whether aberrant c-Fos expression is inherited through functional connectivity and shaped by light experience. Methods: c-Fos+ cell density, functional connectivity, and their experience-dependent modulation were assessed for visual and whole-brain networks in both sexes of 4–6-month-old J20 (AD-model) and wildtype (WT) mice. Cortical and subcortical differences in presynaptic vulnerability in the AD-model were compared using ex vivo and in vivo imaging. Results: Visual cortical, but not subcortical, networks show aberrant c-Fos expression and impaired experience-dependent modulation. The average functional connectivity of a brain region in WT mice significantly predicts aberrant c-Fos expression, which correlates with impaired experience-dependent modulation in the AD-model. We observed a subtle yet selective weakening of excitatory visual cortical synapses. The size distribution of cortical boutons in the AD-model is downscaled relative to those in WT mice, suggesting a synaptic scaling-like adaptation of bouton size. Conclusions: Visual network structural and functional disruptions are biased toward cortical regions in pre-plaque J20 mice, and the cellular and synaptic dysregulation in the AD-model represents a maladaptive modification of the baseline physiology seen in WT conditions. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a degenerative disease of the central nervous system. The pathogenesis is still not fully clear. One of the main histopathological manifestations is senile plaques formed by β-amyloid (Aβ) accumulation. Aβ is generated from the sequential proteolysis of amyloid precursor protein (APP) by β-secretase [i.e. β-site APP cleaving enzyme 1 (BACE1)] and γ-secretase, with a rate-limiting step controlled by BACE1 activity. Therefore, inhibiting BACE1 activity has become a potential therapeutic strategy for AD. The development of reliable detection methods for BACE1 activity plays an important role in early diagnosis of AD and evaluation of the therapeutic effect of new drugs for AD. This article has reviewed the recent advances in BACE1 activity detection techniques. The challenges of applying these analysis techniques to early clinical diagnosis of AD and development trends of the detection techniques have been prospected. [ABSTRACT FROM AUTHOR]

Background: Hereditary transthyretin (ATTRv, v for variant) amyloidosis with polyneuropathy is a rare disease caused by mutations in the transthyretin gene. In ATTRv amyloidosis, multisystem extracellular deposits of amyloid cause tissue and organ dysfunction. Patisiran is a small interfering RNA molecule drug that reduces circulating levels of mutant and wild-type TTR proteins. Prior to its regulatory approval, patisiran was available in Italy through a compassionate use programme (CUP). The aim of this study was to analyse the long-term outcomes of patients who entered into the CUP. Methods: This was a multicentre, observational, retrospective study of patients with ATTRv amyloidosis treated with patisiran. The analysis included change from baseline to 12, 24, 36 and 48 months in familial amyloid polyneuropathy (FAP) stage, polyneuropathy disability (PND) class, neuropathy impairment score (NIS), modified body mass index (mBMI), Compound Autonomic Dysfunction Test (CADT), Karnofsky Performance Status (KPS) scale and Norfolk Quality of Life–Diabetic Neuropathy (QoL-DN) questionnaire. Safety data were also analysed. Results: Forty patients from 11 Italian centres were enrolled: 23 in FAP 1 (6 in PND 1 and 17 in PND 2) and 17 in FAP 2 (8 in PND 3a and 9 in PND 3b) stage. In this population, the mean NIS at baseline was 71.4 (± 27.8); mBMI, 917.1 (± 207) kg/m2; KPS, 67.1 (± 14.0); Norfolk QoL-DN, 62.2 (± 25.2); and CADT, 13.2 (± 3.3). Statistical analysis showed few significant differences from baseline denoting disease stability. No new safety signals emerged. Conclusions: Patisiran largely stabilised disease in patients with ATTRv amyloidosis. [ABSTRACT FROM AUTHOR]

• Silent Alzheimer's disease impacts hypothalamus and hippocampus transcriptome. • AppNL-G-F mice show change in several biomarkers prior to cognitive decline. • Leptin levels are decreased during silent phase of Alzheimer's in AppNL-G-F mice. • Inflammatory mediators are increased during silent phase in AppNL-G-F mice. • Transcriptome changes during the silent phase persists during active disease phase. The progression of Alzheimer's disease (AD) has a silent phase that predates characteristic cognitive decline and eventually leads to active cognitive deficits. Metabolism, diet, and obesity have been correlated to the development of AD but is poorly understood. The hypothalamus is a brain region that exerts homeostatic control on food intake and metabolism and has been noted to be impacted during the active phase of Alzheimer's disease. This study, in using an amyloid overexpression AppNL-G-F mouse model under normal metabolic conditions, examines blood markers in young and old male AppNL-G-F mice (n = 5) that corresponds to the silent and active phases of AD, and bulk gene expression changes in the hypothalamus and the hippocampus. The results show a large panel of inflammatory mediators, leptin, and other proteins that may be involved in weakening the blood brain barrier, to be increased in the young AppNL-G-F mice but not in the old AppNL-G-F mice. There were also several differentially expressed genes in both the hypothalamus and the hippocampus in the young AppNL-G-F mice prior to amyloid plaque formation and cognitive decline that persisted in the old AppNL-G-F mice, including GABRa2 receptor, Wdfy1, and several pseudogenes with unknown function. These results suggests that a larger panel of inflammatory mediators may be used as blood markers to detect silent AD, and that a change in leptin and gene expression in the hypothalamus exist prior to cognitive effects, suggesting a coupling of metabolism with amyloid plaque induced cognitive decline. [ABSTRACT FROM AUTHOR]

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]

An unprecedented extension of life expectancy observed during the past century drastically increased the number of patients diagnosed with Parkinson's diseases (PD) worldwide. Estimated costs of PD alone reached $52 billion per year, making effective neuroprotective treatments an urgent and unmet need. Current treatments of both AD and PD focus on mitigating the symptoms associated with these pathologies and are not neuroprotective. In this review, we discuss the most advanced therapeutic strategies that can be used to treat PD. We also critically review the shift of the therapeutic paradigm from a small molecule-based inhibition of protein aggregation to the utilization of natural degradation pathways and immune cells that are capable of degrading toxic amyloid deposits in the brain of PD patients. [ABSTRACT FROM AUTHOR]

Senile plaques, mainly diffuse, and cerebral amyloid-β (Aβ) angiopathy are prevalent in the aging brain of non-human primates, from lemurs to non-human Hominidae. Aβ but not hyper-phosphorylated tau (HPtau) pathology is the common nominator proteinopathy of non-human primate brain aging. The abundance of Aβ in the aging primate brain is well tolerated, and the impact on cognitive functions is usually limited to particular tasks. In contrast, human brain aging is characterized by the early appearance of HPtau pathology, mainly forming neurofibrillary tangles, dystrophic neurites of neuritic plaques, and neuropil threads, preceding Aβ deposits by several decades and by its severity progressing from selected nuclei of the brain stem, entorhinal cortex, and hippocampus to the limbic system, neocortex, and other brain regions. Neurofibrillary tangles correlate with cognitive impairment and dementia in advanced cases. Aβ pathology is linked in humans to altered membrane protein and lipid composition, particularly involving lipid rafts. Although similar membrane alterations are unknown in non-human primates, membrane senescence is postulated to cause the activated β-amyloidogenic pathway, and Aβ pathology is the prevailing signature of non-human and human primate brain aging. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) accounts for most dementia cases, but we lack a complete understanding of the mechanisms responsible for the core pathology associated with the disease (e.g., amyloid plaque and neurofibrillary tangles). Inflammation has been identified as a key contributor of AD pathology, with recent evidence pointing towards Reelin dysregulation as being associated with inflammation. Here we describe Reelin signaling and outline existing research involving Reelin signaling in AD and inflammation. Research is described pertaining to the inflammatory and immunological functions of Reelin before we propose a mechanism through which inflammation renders Reelin susceptible to dysregulation resulting in the induction and exacerbation of AD pathology. Based on this hypothesis, it is predicted that disorders of both inflammation (including peripheral inflammation and neuroinflammation) and Reelin dysregulation (including disorders associated with upregulated Reelin expression and disorders of Reelin downregulation) have elevated risk of developing AD. We conclude with a description of AD risk in various disorders involving Reelin dysregulation and inflammation. [ABSTRACT FROM AUTHOR]

Episodic memory in older adults is varied and perceived to rely on numbers of synapses or dendritic spines. We analyzed 2157 neurons among 128 older individuals from the Religious Orders Study and Rush Memory and Aging Project. Analysis of 55,521 individual dendritic spines by least absolute shrinkage and selection operator regression and nested model cross-validation revealed that the dendritic spine head diameter in the temporal cortex, but not the premotor cortex, improved the prediction of episodic memory performance in models containing β amyloid plaque scores, neurofibrillary tangle pathology, and sex. These findings support the emerging hypothesis that, in the temporal cortex, synapse strength is more critical than quantity for memory in old age. [ABSTRACT FROM AUTHOR]

Background: Accumulation of advanced glycation end products (AGEs) has contribution in development of Alzheimer's disease (AD), vascular dementia (VAD), and mild cognitive impairment (MCI). AGEs activate several signaling pathways that have roles in development of those diseases via receptor for advanced glycation end product (RAGE), this receptor has its soluble form called sRAGE which has ability to bind AGEs but could not induce molecular signaling. Based on this property, sRAGE could work as RAGE decoy and prevent pathological effect of AGEs accumulation. This meta-analysis is aimed to evaluate correlation between sRAGE plasma level and risk of AD, VAD, and MCI. Methods: Standardized mean difference with 95% coincidence interval was used as effect size. Inverse variance was used as analysis method with random effect model. Egger test and funnel plot were used to assess publication bias. Results: We found 424 articles through database searching. Among those articles, 15 articles that fulfilled our eligibility criteria. After selection based on inclusion and exclusion criteria, only 5 articles were included in this meta-analysis. Our analysis found that AD and VAD patients have lower levels of plasma sRAGE when compared to healthy control. Significant correlation between low sRAGE plasma level and MCI was not found. However, publication bias is found in MCI group. Publication bias of VAD group could not be assessed due to limited number of studies. Conclusions: Here, we show inverse relationship between sRAGE and the incidence of AD alongside VAD suggests that lower sRAGE plasma levels may be associated with a higher incidence of AD and VAD. However, some limitations in sample size and minimal studies may introduce bias into our results. [ABSTRACT FROM AUTHOR]

Multinucleated microglia have been observed in contexts associated with infection, inflammation, and aging. Though commonly linked to pathological conditions, the larger cell size of multinucleated microglia might enhance their phagocytic functions, potentially aiding in the clearance of brain debris and suggesting a reassessment of their pathological significance. To assess the phagocytic capacity of multinucleated microglia and its implications for brain debris clearance, we induced their formation by inhibiting Pyk2 activity using the pharmacological inhibitor PF-431396, which triggers cytokinesis regression. Multinucleated microglia demonstrate enhanced phagocytic function, as evidenced by their increased capacity to engulf β-amyloid (Aβ) oligomers. Concurrently, the phosphorylation of Pyk2, induced by Aβ peptide, was diminished upon treatment with a Pyk2 inhibitor (Pyk2-Inh, PF-431396). Furthermore, the increased expression of Lamp1, a lysosomal marker, with Pyk2-inh treatment, suggests an enhancement in proteolytic activity. In vivo, we generated an acute Alzheimer's disease (AD) model by infusing Aβ into the brains of Iba-1 EGFP transgenic (Tg) mice. The administration of the Pyk2-Inh led to an increased migration of microglia toward amyloid deposits in the brains of Iba-1 EGFP Tg mice, accompanied by morphological activation, suggesting a heightened affinity for Aβ. In human microglia, lipopolysaccharide (LPS)-induced inflammatory responses showed that inhibition of Pyk2 signaling significantly reduced the transcription and protein expression of pro-inflammatory markers. These results suggest that Pyk2 inhibition can modulate microglial functions, potentially reducing neuroinflammation and aiding in the clearance of neurodegenerative disease markers. This highlights Pyk2 as a promising target for therapeutic intervention in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Asymptomatic Alzheimer's disease (AsymAD) describes the status of individuals with preserved cognition but identifiable Alzheimer's disease (AD) brain pathology (i.e., beta-amyloid (Aβ) deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD subjects to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit enrichment in core plaques, decreased filamentous plaque accumulation, and increased plaque-surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD brains than in AD brains, and tau seeding activity was comparable to that in healthy brains. We used spatial transcriptomics to characterize the plaque niche further and revealed autophagy, endocytosis, and phagocytosis as the pathways associated with the genes upregulated in the AsymAD plaque niche. Furthermore, the levels of ARP2 and CAP1, which are actin-based motility proteins that participate in the dynamics of actin filaments to allow cell motility, were increased in the microglia surrounding amyloid plaques in AsymAD cases. Our findings suggest that the amyloid-plaque microenvironment in AsymAD cases is characterized by the presence of microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared with that in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aβ, preserving brain health, and slowing AD pathology progression. [ABSTRACT FROM AUTHOR]

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]

Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by memory and cognitive decline in older individuals. Beta-amyloid (Aβ), a significant component of senile plaques, is recognized as a primary contributor to AD pathology. Hence, substances that can inhibit Aβ production and/or accumulation are crucial for AD prevention and treatment. Agrimonia pilosa LEDEB. (A. pilosa) (Rosaceae), specifically its aerial parts, was identified in our previous screening study as a promising candidate with inhibitory effects on Aβ production. Therefore, in this study, A. pilosa extract was investigated for its anti-amyloidogenic effects, and its bioactive principles were isolated and identified. The ethanol extract of A. pilosa reduced the levels of sAPPβ and β-secretase by approximately 3% and 40%, respectively, compared to the DMSO-treated control group in APP-CHO cells (a cell line expressing amyloid precursor protein), which were similar to those in the positive control group. In addition, the ethanol extract of A. pilosa also hindered Aβ's aggregation into fibrils and facilitated the disaggregation of Aβ aggregates, as confirmed by a Thioflavin T (Th T) assay. Subsequently, the active constituents were isolated using a bioassay-guided isolation method involving diverse column chromatography. Eleven compounds were identified—epi-catechin (1), catechin (2), (2S, 3S)-dihydrokaempferol 3-O-β-D-glucopyranoside (3), (-)-epiafzelechin 5-O-β-D-glucopyranoside (4), kaempferol 3-O-β-D-glucopyranoside (5), apigenin 7-O-β-D-glucopyranoside (6), dihydrokaempferol 7-O-β-D-glucopyranoside (7), quercetin 3-O-β-D-glucopyranoside (8), (2S, 3S)-taxifolin 3-O-β-D-glucopyranoside (9), luteolin 7-O-β-D-glucopyranoside (10), and apigenin 7-O-β-D-methylglucuronate (11)—identified through 1D and 2D NMR analysis and comparison with data from the literature. These compounds significantly decreased Aβ production by reducing β- and γ-secretase levels. Moreover, none of the compounds affected the expression levels of sAPPα or α-secretase. Further, compounds 1, 2, 4, 8, and 10 demonstrated a dose-dependent reduction in Aβ aggregation and promoted the disaggregation of pre-formed Aβ aggregates. Notably, compound 8 inhibited the aggregation of Aβ into fibrils by about 43% and facilitated the disassembly of Aβ aggregates by 41% compared to the control group containing only Aβ. These findings underscore the potential of A. pilosa extract and its constituents to mitigate a crucial pathological aspect of AD. Therefore, A. pilosa extract and its active constituents hold promise for development as therapeutics and preventatives of AD. [ABSTRACT FROM AUTHOR]

Early pathological upregulation of adenosine A2A receptors (A2ARs), one of the caffeine targets, by neurons is thought to be involved in the development of synaptic and memory deficits in Alzheimer's disease (AD) but mechanisms remain ill-defined. To tackle this question, we promoted a neuronal upregulation of A2AR in the hippocampus of APP/PS1 mice developing AD-like amyloidogenesis. Our findings revealed that the early upregulation of A2AR in the presence of an ongoing amyloid pathology exacerbates memory impairments of APP/PS1 mice. These behavioural changes were not linked to major change in the development of amyloid pathology but rather associated with increased phosphorylated tau at neuritic plaques. Moreover, proteomic and transcriptomic analyses coupled with quantitative immunofluorescence studies indicated that neuronal upregulation of the receptor promoted both neuronal and non-neuronal autonomous alterations, i.e. enhanced neuroinflammatory response but also loss of excitatory synapses and impaired neuronal mitochondrial function, presumably accounting for the detrimental effect on memory. Overall, our results provide compelling evidence that neuronal A2AR dysfunction, as seen in the brain of patients, contributes to amyloid-related pathogenesis and underscores the potential of A2AR as a relevant therapeutic target for mitigating cognitive impairments in this neurodegenerative disorder. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is the primary neurodegenerative disease affecting the elderly population. Despite the first description of its pathology over a century ago, its precise cause and molecular mechanism remain unknown. Numerous factors, including beta-amyloid, tau protein, the APOEε4 gene, and different metals, have been extensively investigated in relation to this disease. However, none of them have been proven to have a decisive causal relationship. Furthermore, no single theory has successfully integrated these puzzle pieces thus far. In this review article, we propose the most probable molecular mechanism for AD, which clearly shows the relationship between the main aspects of the disease, and addresses fundamental questions such as: Why is aging the major risk factor for the disease? Are amyloid plaques and tau tangles the causes or consequences of AD? Why are the distributions of senile plaques and tau tangles in the brain different and independent of each other? Why is the APOEε4 gene a risk factor for AD? Finally, why is the disease more prevalent in women? [ABSTRACT FROM AUTHOR]

Betanin, a natural compound with anti-inflammatory and antioxidant properties, has shown promise in mitigating Alzheimer's disease (AD) by reducing amyloid plaque production. Employing network pharmacology, this study aimed to elucidate betanin's therapeutic mechanism in AD treatment. Through integrated analyses utilizing SwissTargetPrediction, STITCH, BindingDB, Therapeutic Target Database (TTD), and OMIM databases, potential protein targets of betanin in AD were predicted. Gene ontology analysis facilitated the identification of 49 putative AD targets. Subsequent gene enrichment and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis revealed associations between these targets and AD. Network pharmacology techniques and molecular docking aided in prioritizing essential genes, with APP, CASP7, ITPR1, CASP8, CASP3, ITPR3, and NF-KB1 emerging as top candidates. The results provide novel insights into betanin's therapeutic efficacy, shedding light on its potential clinical application in AD treatment. By targeting key genes implicated in AD pathology, betanin demonstrates promise as a valuable addition to existing therapeutic strategies. This holistic approach emphasizes the relevance of network pharmacology and bioinformatics analysis in understanding natural chemical disease therapy processes. [ABSTRACT FROM AUTHOR]

"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]

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]

Brain alpha-tocopherol (αT) concentration was previously reported to be inversely associated with neurofibrillary tangle (NFT) counts in specific brain structures from centenarians. However, the contribution of natural or synthetic αT stereoisomers to this relationship is unknown. In this study, αT stereoisomers were quantified in the temporal cortex (TC) of 47 centenarians in the Georgia Centenarian Study (age: 102.2 ± 2.5 years, BMI: 22.1 ± 3.9 kg/m2) and then correlated with amyloid plaques (diffuse and neuritic plaques; DPs, NPs) and NFTs in seven brain regions. The natural stereoisomer, RRR-αT, was the primary stereoisomer in all subjects, accounting for >50% of total αT in all but five subjects. %RRR was inversely correlated with DPs in the frontal cortex (FC) (ρ = −0.35, p = 0.032) and TC (ρ = −0.34, p = 0.038). %RSS (a synthetic αT stereoisomer) was positively correlated with DPs in the TC (ρ = 0.39, p = 0.017) and with NFTs in the FC (ρ = 0.37, p = 0.024), TC (ρ = 0.42, p = 0.009), and amygdala (ρ = 0.43, p = 0.008) after controlling for covariates. Neither RRR- nor RSS-αT were associated with premortem global cognition. Even with the narrow and normal range of BMIs, BMI was correlated with %RRR-αT (ρ = 0.34, p = 0.021) and %RSS-αT (ρ = −0.45, p = 0.002). These results providing the first characterization of TC αT stereoisomer profiles in centenarians suggest that DP and NFT counts, but not premortem global cognition, are influenced by the brain accumulation of specific αT stereoisomers. Further study is needed to confirm these findings and to determine the potential role of BMI in mediating this relationship. [ABSTRACT FROM AUTHOR]

Amyloid plaques and tau tangles are the hallmark pathologic features of Alzheimer's disease (AD). Traditionally, these changes are identified in vivo via cerebrospinal fluid (CSF) analysis or positron emission tomography (PET) scans. However, these methods are invasive, expensive, and resource-intensive. To address these limitations, there has been ongoing research over the past decade to identify blood-based markers for AD. Despite the challenges posed by their extremely low concentrations, recent advances in mass spectrometry and immunoassay techniques have made it feasible to detect these blood markers of amyloid and tau deposition. Phosphorylated tau (p-tau) has shown greater promise in reflecting amyloid pathology as evidenced by CSF and PET positivity. Various isoforms of p-tau, distinguished by their differential phosphorylation sites, have been recognized for their ability to identify amyloid-positive individuals. Notable examples include p-tau181, p-tau217, and p-tau235. Among these, p-tau217 has emerged as a superior and reliable marker of amyloid positivity and, thus, AD in terms of accuracy of diagnosis and ability for early prognosis. In this narrative review, we aim to elucidate the utility of p-tau217 as an AD marker, exploring its underlying basis, clinical diagnostic potential, and relevance in clinical care and trials. [ABSTRACT FROM AUTHOR]

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]

A relationship between poor oral health conditions and cognitive decline has been clinically observed. A bidirectional association between periodontitis and Alzheimer's disease has been repeatedly identified in clinical and pre-clinical studies. This association is supported by four major overlapped pathways and mechanisms, including the microbiota-gut-brain axis via the vagus nerve pathway, periodontopathogen-involved neuroinflammation via the trigeminal nerve pathway, proinflammatory cytokines, and trained immunity. Partly linked with periodontitis, increased levels of proinflammatory cytokines and decreased levels of anti-inflammatory cytokines can exacerbate the abnormal accumulation of amyloid beta plaques and hyperphosphorylation of tau protein. Periodontitis is considered an important environmental factor involved in Alzheimer's disease development. This review discusses the bidirectional relationship between Alzheimer's disease and periodontitis, focusing on the association between cognitive decline and poor oral health conditions. Thus, oral health intervention strategies have been proposed as potential therapeutic methods for the prevention and management of Alzheimer's disease. [Psychiatr Ann. 2024;54(8):e230–e234.] [ABSTRACT FROM AUTHOR]

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]

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, and the most prevalent form of dementia. The main hallmarks for the diagnosis of AD are extracellular amyloid-beta (Aβ) plaque deposition and intracellular accumulation of highly hyperphosphorylated Tau protein as neurofibrillary tangles. The brain consumes more oxygen than any other organs, so it is more easily to be affected by hypoxia. Hypoxia has long been recognized as one of the possible causes of AD and other neurodegenerative diseases, but the exact mechanism has not been clarified. In this review, we will elucidate the connection between hypoxia-inducible factors-1α and AD, including its contribution to AD and its possible protective effects. Additionally, we will discuss the relationship between oxidative stress and AD as evidence show that oxidative stress acts on AD-related pathogenic factors such as mitochondrial dysfunction, Aβ deposition, inflammation, etc. Currently, there is no cure for AD. Given the close association between hypoxia, oxidative stress, and AD, along with current research on the protective effects of antioxidants against AD, we speculate that antioxidants could be a potential therapeutic approach for AD and worth further study. [ABSTRACT FROM AUTHOR]

Background: Alpha-lipoic acid (ALA) has a neuroprotective effect on neurodegenerative diseases. In the clinic, ALA can improve cognitive impairments in patients with Alzheimer's disease (AD) and other dementias. Animal studies have confirmed the anti-amyloidosis effect of ALA, but its underlying mechanism remains unclear. In particular, the role of ALA in amyloid-β precursor protein (APP) metabolism has not been fully elucidated. Objective: To investigate whether ALA can reduce the amyloidogenic effect of APP in a transgenic mouse model of AD, and to study the mechanism underlying this effect. Methods: ALA was infused into 2-month-old APP23/PS45 transgenic mice for 4 consecutive months and their cognitive function and AD-like pathology were then evaluated. An ALA drug concentration gradient was applied to 20E2 cells in vitro to evaluate its effect on the expression of APP proteolytic enzymes and metabolites. The mechanism by which ALA affects APP processing was studied using GI254023X, an inhibitor of A Disintegrin and Metalloproteinase 10 (ADAM10), as well as the mitochondrial toxic drug carbonyl cyanide m-chlorophenylhydrazone (CCCP). Results: Administration of ALA ameliorated amyloid plaque neuropathology in the brain tissue of APP23/PS45 mice and reduced learning and memory impairment. ALA also increased the expression of ADAM10 in 20E2 cells and the non-amyloidogenic processing of APP to produce the 83 amino acid C-terminal fragment (C83). In addition to activating autophagy, ALA also significantly promoted mitophagy. BNIP3L-knockdown reduced the mat/pro ratio of ADAM10. By using CCCP, ALA was found to regulate BNIP3L-mediated mitophagy, thereby promoting the α-cleavage of APP. Conclusions: The enhanced α-secretase cleavage of APP by ADAM10 is the primary mechanism through which ALA ameliorates the cognitive deficits in APP23/PS45 transgenic mice. BNIP3L-mediated mitophagy contributes to the anti-amyloid properties of ALA by facilitating the maturation of ADAM10. This study provides novel experimental evidence for the treatment of AD with ALA. [ABSTRACT FROM AUTHOR]

Background: The heightened risk of cardiovascular and cerebrovascular events is associated with the increased instability of atherosclerotic plaques. However, the lack of effective diagnostic biomarkers has impeded the assessment of plaque instability currently. This study was aimed to investigate and identify hub genes associated with unstable plaques through the integration of various bioinformatics tools, providing novel insights into the detection and treatment of this condition. Methods: Weighted Gene Co-expression Network Analysis (WGCNA) combined with two machine learning methods were used to identify hub genes strongly associated with plaque instability. The cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) method was utilized to assess immune cell infiltration patterns in atherosclerosis patients. Additionally, Gene Set Variation Analysis (GSVA) was conducted to investigate the potential biological functions, pathways, and mechanisms of hub genes associated with unstable plaques. To further validate the diagnostic efficiency and expression of the hub genes, immunohistochemistry (IHC), quantitative real-time polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA) were performed on collected human carotid plaque and blood samples. Immunofluorescence co-staining was also utilized to confirm the association between hub genes and immune cells, as well as their colocalization with mitochondria. Results: The CIBERSORT analysis demonstrated a significant decrease in the infiltration of CD8 T cells and an obvious increase in the infiltration of M0 macrophages in patients with atherosclerosis. Subsequently, two highly relevant modules (blue and green) strongly associated with atherosclerotic plaque instability were identified. Through intersection with mitochondria-related genes, 50 crucial genes were identified. Further analysis employing least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine recursive feature elimination (SVM-RFE) algorithms revealed six hub genes significantly associated with plaque instability. Among them, NT5DC3, ACADL, SLC25A4, ALDH1B1, and MAOB exhibited positive correlations with CD8 T cells and negative correlations with M0 macrophages, while kynurenine 3-monooxygenas (KMO) demonstrated a positive correlation with M0 macrophages and a negative correlation with CD8 T cells. IHC and RT-qPCR analyses of human carotid plaque samples, as well as ELISA analyses of blood samples, revealed significant upregulation of KMO and MAOB expression, along with decreased ALDH1B1 expression, in both stable and unstable samples compared to the control samples. However, among the three key genes mentioned above, only KMO showed a significant increase in expression in unstable plaque samples compared to stable plaque samples. Furthermore, the expression patterns of KMO in human carotid unstable plaque tissues and cultured mouse macrophage cell lines were assessed using immunofluorescence co-staining techniques. Finally, lentivirus-mediated KMO silencing was successfully transduced into the aortas of high-fat-fed ApoE-/- mice, with results indicating that KMO silencing attenuated plaque formation and promoted plaque stability in ApoE-/- mice. Conclusions: The results suggest that KMO, a mitochondria-targeted gene associated with macrophage cells, holds promise as a valuable diagnostic biomarker for assessing the instability of atherosclerotic plaques. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common sort of neurodegenerative dementia, characterized by its challenging, diverse, and progressive nature. Despite significant progress in neuroscience, the current treatment strategies remain suboptimal. Objective: Identifying a more accurate molecular target for the involvement of microglia in the pathogenic process of AD and exploring potential mechanisms via which it could influence disease. Methods: We utilized single-cell RNA sequencing (scRNA-seq) analysis in conjunction with APP/PS1 mouse models to find out the molecular mechanism of AD. With the goal of investigating the cellular heterogeneity of AD, we downloaded the scRNA-seq data from the Gene Expression Omnibus (GEO) database and identified differentially expressed genes (DEGs). Additionally, we evaluated learning and memory capacity using the behavioral experiment. We also examined the expression of proteins associated with memory using western blotting. Immunofluorescence was employed to investigate alterations in amyloid plaques and microglia. Results: Our findings revealed an upregulation of ITGAX expression in APP/PS1 transgenic mice, which coincided with a downregulation of synaptic plasticity-related proteins, an increase in amyloid-β (Aβ) plaques, and an elevation in the number of M1 microglia. Interestingly, deletion of ITGAX resulted in increased Aβ plaque deposition, a rise in the M1 microglial phenotype, and decreased production of synaptic plasticity-related proteins, all of which contributed to a decline in learning and memory. Conclusions: This research suggested that ITGAX may have a beneficial impact on the APP/PS1 mice model, as its decreased expression could exacerbate the impairment of synaptic plasticity and worsen cognitive dysfunction. [ABSTRACT FROM AUTHOR]

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]

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]

Introduction: Dual specificity protein phosphatase 6 (DUSP6) was recently identified as a key hub gene in a causal VGF gene network that regulates late-onset Alzheimer's disease (AD). Importantly, decreased DUSP6 levels are correlated with an increased clinical dementia rating (CDR) in human subjects, and DUSP6 levels are additionally decreased in the 5xFAD amyloidopathy mouse model. Methods: To investigate the role of DUSP6 in AD, we stereotactically injected AAV5-DUSP6 or AAV5-GFP (control) into the dorsal hippocampus (dHc) of both female and male 5xFAD or wild type mice, to induce overexpression of DUSP6 or GFP. Results: Barnes maze testing indicated that DUSP6 overexpression in the dHc of 5xFAD mice improved memory deficits and was associated with reduced amyloid plaque load, Aß1-40 and Aß1-42 levels, and amyloid precursor protein processing enzyme BACE1, in male but not in female mice. Microglial activation, which was increased in 5xFAD mice, was significantly reduced by dHc DUSP6 overexpression in both males and females, as was the number of "microglial clusters," which correlated with reduced amyloid plaque size. Transcriptomic profiling of female 5xFAD hippocampus revealed upregulation of inflammatory and extracellular signal-regulated kinase pathways, while dHc DUSP6 overexpression in female 5xFAD mice downregulated a subset of genes in these pathways. Gene ontology analysis of DEGs (p < 0.05) identified a greater number of synaptic pathways that were regulated by DUSP6 overexpression in male compared to female 5xFAD. Discussion: In summary, DUSP6 overexpression in dHc reduced amyloid deposition and memory deficits in male but not female 5xFAD mice, whereas reduced neuroinflammation and microglial activation were observed in both males and females, suggesting that DUSP6-induced reduction of microglial activation did not contribute to sex-dependent improvement in memory deficits. The sex-dependent regulation of synaptic pathways by DUSP6 overexpression, however, correlated with the improvement of spatial memory deficits in male but not female 5xFAD. [ABSTRACT FROM AUTHOR]

The classical amyloid cascade hypothesis postulates that the aggregation of amyloid plaques and the accumulation of intracellular hyperphosphorylated Tau tangles, together, lead to profound neuronal death. However, emerging research has demonstrated that soluble amyloid-β oligomers (SAβOs) accumulate early, prior to amyloid plaque formation. SAβOs induce memory impairment and disrupt cognitive function independent of amyloid-β plaques, and even in the absence of plaque formation. This work describes the development and characterization of a novel anti-SAβO (E3) nanobody generated from an alpaca immunized with SAβO. In-vitro assays and in-vivo studies using 5XFAD mice indicate that the fluorescein (FAM)-labeled E3 nanobody recognizes both SAβOs and amyloid-β plaques. The E3 nanobody traverses across the blood–brain barrier and binds to amyloid species in the brain of 5XFAD mice. Imaging of mouse brains reveals that SAβO and amyloid-β plaques are not only different in size, shape, and morphology, but also have a distinct spatial distribution in the brain. SAβOs are associated with neurons, while amyloid plaques reside in the extracellular matrix. The results of this study demonstrate that the SAβO nanobody can serve as a diagnostic agent with potential theragnostic applications in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Metabolism is increasingly recognized as a key regulator of the function and phenotype of the primary cellular constituents of the atherosclerotic vascular wall, including endothelial cells, smooth muscle cells, and inflammatory cells. However, a comprehensive analysis of metabolic changes associated with the transition of plaque from a stable to a hemorrhaged phenotype is lacking. Methods: In this study, we integrated two large mRNA expression and protein abundance datasets (BIKE, n = 126; MaasHPS, n = 43) from human atherosclerotic carotid artery plaque to reconstruct a genome-scale metabolic network (GEM). Next, the GEM findings were linked to metabolomics data from MaasHPS, providing a comprehensive overview of metabolic changes in human plaque. Results: Our study identified significant changes in lipid, cholesterol, and inositol metabolism, along with altered lysosomal lytic activity and increased inflammatory activity, in unstable plaques with intraplaque hemorrhage (IPH+) compared to non-hemorrhaged (IPH−) plaques. Moreover, topological analysis of this network model revealed that the conversion of glutamine to glutamate and their flux between the cytoplasm and mitochondria were notably compromised in hemorrhaged plaques, with a significant reduction in overall glutamate levels in IPH+ plaques. Additionally, reduced glutamate availability was associated with an increased presence of macrophages and a pro-inflammatory phenotype in IPH+ plaques, suggesting an inflammation-prone microenvironment. Conclusions: This study is the first to establish a robust and comprehensive GEM for atherosclerotic plaque, providing a valuable resource for understanding plaque metabolism. The utility of this GEM was illustrated by its ability to reliably predict dysregulation in the cholesterol hydroxylation, inositol metabolism, and the glutamine/glutamate pathway in rupture-prone hemorrhaged plaques, a finding that may pave the way to new diagnostic or therapeutic measures. [ABSTRACT FROM AUTHOR]