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TMEM16F is involved in many physiological processes such as blood coagulation, cell membrane fusion and bone mineralization. Activation of TMEM16F has been studied in various central nervous system diseases. High TMEM16F level has been also found to participate in microglial phagocytosis and transformation. Microglia-mediated neuroinflammation is a key factor in promoting the progression of Alzheimer’s disease. However, few studies have examined the effects of TMEM16F on neuroinflammation in Alzheimer’s disease. In this study, we established TMEM16F-knockdown AD model in vitro and in vivo to investigate the underlying regulatory mechanism about TMEM16F-mediated neuroinflammation in AD. We performed a Morris water maze test to evaluate the spatial memory ability of animals and detected markers for the microglia M1/M2 phenotype and NLRP3 inflammasome. Our results showed that TMEM16F was elevated in 9-month-old APP/PS1 mice. After TMEM16F knockdown in mice, spatial memory ability was improved, microglia polarization to the M2 phenotype was promoted, NLRP3 inflammasome activation was inhibited, cell apoptosis and Aβ plaque deposition in brain tissue were reduced, and brain injury was alleviated. We used amyloid-beta (Aβ25–35) to stimulate human microglia to construct microglia models of Alzheimer’s disease. The levels of TMEM16F, inducible nitric oxide synthase (iNOS), proinflammatory cytokines and NLRP3 inflammasome-associated biomarkers were higher in Aβ25–35 treated group compared with that in the control group. TMEM16F knockdown enhanced the expression of the M2 phenotype biomarkers Arg1 and Socs3, reduced the release of proinflammatory factors interleukin-1, interleukin-6 and tumor necrosis factor-α, and inhibited NLRP3 inflammasome activation through reducing downstream proinflammatory factors interleukin-1β and interleukin-18. This inhibitory effect of TMEM16F knockdown on M1 microglia was partially reversed by the NLRP3 agonist Nigericin. Our findings suggest that TMEM16F participates in neuroinflammation in Alzheimer’s disease through participating in polarization of microglia and activation of the NLRP3 inflammasome. These results indicate that TMEM16F inhibition may be a potential therapeutic approach for Alzheimer’s disease treatment.

Alzheimer's disease (AD) is the most prevalent form of dementia, but no effective therapeutic strategy is available to date. Rhythmic magnetic stimulation is an attractive means of neuron modulation that could be beneficial for restoring learning and memory abilities. To assess the effect of a compound pulsed rhythmic magnetic field (cPMF) on cognition during AD progression and to explore the appropriate cPMF intervention period. Female 5xFAD mice aged 10 weeks and 18 weeks were exposed to cPMF with a carrier frequency of 40 Hz, repeated at 5 Hz for 1 h/d for 8 consecutive weeks. The Morris water maze (MWM) test was used for cognitive behavioral assessment. Furthermore, changes in molecular pathology within the brain were detected using immunofluorescence staining and real-time PCR. 10-week-old AD mice treated with cPMF explored the target quadrant more frequently than sham-exposed AD mice in MWM test, exhibiting improved learning and memory abilities. Additionally, cPMF exposure alleviated Aβ plaque deposition and astrogliosis in the AD brain. Moreover, neurotrophic factor fibroblast growth factor 1 (FGF1) in the AD brain was upregulated by cPMF treatment. However, in 18-week-old AD mice treated with cPMF, cognitive performance and Fgf1 gene expression were not significantly improved, although Aβ plaque deposition and astrogliosis were alleviated. Early intervention via long-term rhythmic cPMF stimulation may alleviate the histopathological features and enhance neuroprotective gene Fgf1 expression, thereby improving the cognitive performance of 5xFAD mice, which should provide promising insight for the clinical treatment of patients with AD. • Magnetic stimulation with θ rhythm-modulated γ frequency could enhance the learning and memory abilities of 5xFAD mice. • Early rather than late intervention via the cPMF could improve the cognitive behavioral performance of AD mice. • Both early and late cPMF treatments could alleviate Aβ plaque deposition and astrogliosis of AD mice. • Effectiveness of early cPMF intervention might be attributed to the enhanced expression level of neuroprotective Fgf1 gene. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a great challenge for the world and hardly to be cured, partly because of the lack of animal models that fully mimic pathological progress. Recently, a rat model exhibiting the most pathological symptoms of AD has been reported. However, high-resolution imaging and accurate quantification of beta-amyloid (Ab) plaques in the whole rat brain have not been fulfilled due to substantial technical challenges. In this paper, a high-efficiency data analysis pipeline is proposed to quantify Ab plaques in whole rat brain through several terabytes of image data acquired by a high-speed volumetric imaging approach we have developed previously. A novel segmentation framework applying a highperformance weakly supervised learning method which can dramatically reduce the human labeling consumption is described in this study. The effectiveness of our segmentation framework is validated with different metrics. The segmented Ab plaques were mapped to a standard rat brain atlas for quantitative analysis of the Ab distribution in each brain area. This pipeline may also be applied to the segmentation and accurate quantification of other non-specific morphology objects. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), an age-dependent neurodegenerative disorder, is the most prevalent neurodegenerative disease worldwide. The primary pathological hallmarks of AD are the deposition of β-amyloid plaques and neurofibrillary tangles. Autophagy, a pathway of clearing damaged organelles, macromolecular aggregates, and long-lived proteins via lysosomal degradation, has emerged as critical for proteostasis in the central nervous system (CNS). Studies have demonstrated that defective autophagy is strongly implicated in AD pathogenesis. Transcription factor EB (TFEB), a master transcriptional regulator of autophagy, enhances the expression of related genes that control autophagosome formation, lysosome function, and autophagic flux. The study of TFEB has greatly increased over the last decade, and the dysfunction of TFEB has been reported to be strongly associated with the pathogenesis of many neurodegenerative disorders, including AD. Here, we delineate the basic understanding of TFEB dysregulation involved in AD pathogenesis, highlighting the existing work that has been conducted on TFEB-mediated autophagy in neurons and other nonneuronal cells in the CNS. Additionally, we summarize the small molecule compounds that target TFEB-regulated autophagy involved in AD therapy. Our review may yield new insights into therapeutic approaches by targeting TFEB and provide a broadly applicable basis for the clinical treatment of AD.

Alzheimer’s disease (AD) is characterized by the abnormal deposition of amyloid-β (Aβ) plaques and tau tangles in the brain and accompanied with cognitive impairment. However, the fundamental cause of this disease remains elusive. To elucidate the molecular processes related to AD, we carried out an integrated analysis utilizing gene expression microarrays (GSE36980 and GSE5281) and DNA methylation microarray (GSE66351) in temporal cortex of AD patients from the Gene Expression Omnibus (GEO) database. We totally discovered 409 aberrantly methylated and differentially expressed genes. These dysregulated genes were significantly enriched in biological processes including cell part morphogenesis, chemical synaptic transmission and regulation of Aβ formation. Through convergent functional genomic (CFG) analysis, expression cross-validation and clinicopathological correlation analysis, higher TGFBR3 level was observed in AD and positively correlated with Aβ accumulation. Meanwhile, the promoter methylation level of TGFBR3 was reduced in AD and negatively associated with Aβ level and advanced Braak stage. Mechanically, TGFBR3 might promote Aβ production by enhancing β- and γ-secretase activities. Further investigation revealed that TGFBR3 may exert its functions via Synaptic vesicle cycle, Calcium signaling pathway and MAPK signal pathway by regulating hub genes GNB1, GNG3, CDC5L, DYNC1H1 and FBXW7. Overall, our findings highlighted TGFBR3 as an AD risk gene and might be used as a diagnostic biomarker and therapeutic target for AD treatment.

Importance: Alzheimer's disease (AD) is the most common cause of dementia in the elderly with the incidence rising exponentially after the age of 65 years. Unfortunately, effective treatments are extremely limited and definite diagnosis can only be made at autopsy. This is in part due to our limited understanding of the complex pathophysiology, including the various genetic, environmental, and metabolic contributing factors. In an effort to better understand this complex disease, researchers have employed nonhuman primates as translational models., Case Presentation: This report aims to describe the AD-like neuropathology in the brain of a 37-year-old female baboon ( Papio hamadryas ), which at the time of her death made her the oldest hamadryas baboon at any member institution of the Association of Zoos and Aquariums. A diagnostic necropsy was performed, and the brain was evaluated for neurodegenerative disease. Frequent amyloid-β deposits were identified, consistent with what has been described in other geriatric nonhuman primates. Phospho-tau pathology, including neurofibrillary tangles, a feature not well-described in other primate models, was also abundant., Conclusions and Relevance: Our results suggest that more detailed, prospective, longitudinal studies are warranted utilizing this particular species to see if they represent a viable model for human brain aging., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Korean Society of Veterinary Science.)

FAM19A5, a novel secretory protein highly expressed in the brain, is potentially associated with the progression of Alzheimer's disease (AD). However, its role in the AD pathogenesis remains unclear. Here, we investigated the potential function of FAM19A5 in the context of AD. We generated APP/PS1 mice with partial FAM19A5 deficiency, termed APP/PS1/FAM19A5 +/LacZ mice. Compared with control APP/PS1 mice, APP/PS1/FAM19A5 +/LacZ mice exhibited significantly lower Aβ plaque density and prolonged the lifespan of the APP/PS1 mice. To further explore the therapeutic potential of targeting FAM19A5, we developed a FAM19A5 antibody. Administration of this antibody to APP/PS1 mice significantly improved their performance in the Y-maze and passive avoidance tests, indicating enhanced cognitive function. This effect was replicated in 5XFAD mice, a model of early-onset AD characterized by rapid Aβ accumulation. Additionally, FAM19A5 antibody treatment in 5XFAD mice led to enhanced exploration of novel objects and increased spontaneous alternation behavior in the novel object recognition and Y-maze tests, respectively, indicating improved cognitive function. These findings suggest that FAM19A5 plays a significant role in AD pathology and that targeting with FAM19A5 antibodies may be a promising therapeutic strategy for AD.

Alzheimer's disease (AD) is the most common neurodegenerative disease. It is known to be a multifactorial disease and several causes are associated with its occurrence as well as progression. However, the accumulation of amyloid beta (Aβ) is widely considered its major pathogenic hallmark. Additionally, neurofibrillary tangles (NFT), mitochondrial dysfunction, oxidative stress, and aging (cellular senescence) are considered as additional hits affecting the disease pathology. Several studies are now suggesting important role of inflammation in AD, which shifts our thought towards the brain's resident immune cells, microglia, and astrocytes; how they interact with neurons; and how these interactions are affected by intra and extracellular stressful factors. These interactions can be modulated by different mechanisms and pathways, in which exosomes could play an important role. Exosomes are multivesicular bodies secreted by nearly all types of cells. The exosomes secreted by glial cells or neurons affect the interactions and thus the physiology of these cells by transmitting miRNAs, proteins, and lipids. Exosomes can serve as a friend or foe to the neuron function, depending upon the carried signals. Exosomes, from the healthy microenvironment, may assist neuron function and health, whereas, from the stressed microenvironment, they carry oxidative and inflammatory signals to the neurons and thus prove detrimental to the neuronal function. Furthermore, exosomes can cross the blood–brain barrier (BBB), and from the blood plasma they can enter the brain cells and activate microglia and astrocytes. Exosomes can transport Aβ or Tau, cytokines, miRNAs between the cells, and alter the physiology of recipient cells. They can also assist in Aβ clearance and regulation of synaptic activity. The exosomes derived from different cells play different roles, and this field is still in its infancy stage. This review advocates exosomes' role as a friend or foe in neurodegenerative diseases, especially in the case of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Some studies have implied the damaging effect of sevoflurane (sevo) on cognitive function in Alzheimer's disease (AD). This research was conducted to explore the effect of microRNA (miR)-132/forkhead-box A1 (FOXA1) axis on cognitive ability of sevo-treated AD rats. The condensed-matter Aβ 1 – 40 -induced AD rats were injected with miR-132- or FOXA1-related plasmids, followed by inhalation with 3% sevo. Then, the cognitive functions of AD rats were assessed. miR-132 and FOXA1 levels in hippocampal tissues of AD rats, and their interaction were identified. miR-132 expression was reduced and FOXA1 mRNA and protein levels were elevated in AD rats. miR-132 targeted FOXA1. Sevo treatment impaired cognitive function in AD rats. Elevated miR-132 or inhibited FOXA1 attenuated sevo-mediated injury in AD rats. Overexpressed FOXA1 rescued the effect of elevated miR-132 in AD rats with sevo treatment. Up-regulated miR-132 reduces the cognition-damaging effect of sevo on AD rats by inhibiting FOXA1. • miR-132 level is decreased while FOXA1 mRNA and protein levels are elevated in AD. • Sevo restrains miR-132 and promotes FOXA1 in hippocampus of AD rats. • Sevo accelerates the apoptosis of hippocampal neurons in AD rats. • Elevated miR-132 and reduced FOXA1 relieve sevo-induced cognitive impairment. • Elevated FOXA1 rescues the effect of miR-132 in AD rats with sevo treatment. [ABSTRACT FROM AUTHOR]

Microbes like viruses, bacteria, and fungi have all been reported in the brain of Alzheimer's postmortem patients and/or AD mouse model; however, the relationship between brain microbes and Aβ plaque deposition remains to be elucidated. In the present study, we first analyzed bacteria populations in the brain of 4-, 5-, and 6-month-old APP/PS1 mice and then examined the Aβ-positive loads of APP/PS1 mouse at 9 months old to identify bacteria in the brain by 16S rDNA sequencing. Finally, blood–brain barrier permeability was measured by injecting dextrans through the tail vein. Surprisingly, the diversity of microbial community gradually decreased in APP/PS1 mouse while wild-type mouse showed no obvious regularity. Moreover, Aβ-positive deposits in the brain showed a significantly higher relative abundance of microbiota than Aβ-negative tissues and age-matched wild-type mouse brain tissues. In addition, an increase in blood–brain barrier permeability was also observed in APP/PS1 mouse. The present study revealed the exact location of microbes within the Aβ plaques in the brain and suggested the potential antimicrobial effect of the Aβ peptide. We strongly recommend that future research on microbiota-related AD pathology should focus on the migration route of microbiota into the brain and how the microbiota enhance AD progression. [ABSTRACT FROM AUTHOR]

Brain capillaries are crucial for cognitive functions by supplying oxygen and other nutrients to and removing metabolic wastes from the brain. Recent studies have demonstrated that constriction of brain capillaries is triggered by beta-amyloid (Aβ) oligomers via endothelin-1 (ET1)-mediated action on the ET1 receptor A (ETRA), potentially exacerbating Aβ plaque deposition, the primary pathophysiology of Alzheimer's disease (AD). However, direct evidence is still lacking whether changes in brain capillaries are causally involved in the pathophysiology of AD. Using APP/PS1 mouse model of AD (AD mice) relative to age-matched negative littermates, we identified that reductions of density and diameter of hippocampal capillaries occurred from 4 to 7 months old while Aβ plaque deposition and spatial memory deficit developed at 7 months old. Notably, the injection of ET1 into the hippocampus induced early Aβ plaque deposition at 5 months old in AD mice. Conversely, treatment of ferulic acid against the ETRA to counteract the ET1-mediated vasoconstriction for 30 days prevented reductions of density and diameter of hippocampal capillaries as well as ameliorated Aβ plaque deposition and spatial memory deficit at 7 months old in AD mice. Thus, these data suggest that reductions of density and diameter of hippocampal capillaries are crucial for initiating Aβ plaque deposition and spatial memory deficit at the early stages, implicating the development of new therapies for halting or curing memory decline in AD. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a gradually rising metabolic disease which is currently affecting millions of people worldwide. Diabetes is associated with various complications like nephropathy, neuropathy, retinopathy, diabetic foot, cognitive impairment, and many more. Evidence suggests that cognitive dysfunction is a rising complication of diabetes which adversely affects the brain of patients suffering from diabetes. Age‐related memory impairment is a complication having its major effect on people suffering from diabetes and Alzheimer's. Patients suffering from diabetes are at two times higher risk of developing cognitive dysfunction as compared with normal individuals. Multiple factors which are involved in diabetes related complications are found to play a role in the development of neurodegeneration in Alzheimer's. The problem of insulin deficiency and insulin resistance is well reported in diabetes but there are many studies which suggest dysregulation of insulin levels as a reason behind the development of Alzheimer's. As the link between diabetes and Alzheimer disease (AD) is deepening, there is a need to understand the plausible tie‐ins between the two. Emerging role of major factors like insulin imbalance, advanced glycation end products and micro‐RNA's involved in diabetes and Alzheimer's have been discussed here. This review helps in understanding the plausible mechanism underlying the pathophysiology of amyloid beta (Aβ) plaque formation and tau hyperphosphorylation as well provides information about studies carried out in this area of research. The final thought is to enhance the scientific knowledge on this correlation and develop future therapeutics to treat the same. [ABSTRACT FROM AUTHOR]

Abstract Background Microglia are known as resident immune cells in the brain. β-amyloid (Aβ) plaques in the brain of Alzheimer’s disease (AD) are surrounded by microglia, but whether and how microglia affect the formation and maintenance of plaques remains controversial. Methods We depleted microglia by injecting diphtheria toxin (DT) in CX 3 CR1 CreER/+ :R26 DTR/+ (CX 3 CR1-iDTR) mice crossed with APPswe/PSEN1dE9 (APP/PS1) mice. Intravital time-lapse imaging was performed to examine changes in the number and size of Congo Red-labeled amyloid plaques over 1–2 weeks. We also examined spine density and shaft diameter of dendrites passing through plaques in a PSAPP mouse model of AD (PS1 M146L line 6.2 × Tg2576) crossed with Thy1 YFP H-line mice. Results We found that DT administration to CX 3 CR1-iDTR mice efficiently ablated microglia within one week and that microglia repopulated in the second week after DT administration. Microglia depletion didn’t affect the number of amyloid plaques, but led to ~13% increase in the size of Aβ plaques within one week. Moreover, microglia repopulation was associated with the stabilization of plaque size during the second week. In addition, we found dendritic spine loss and shaft atrophy in the distal parts of dendrites passing through plaques. Conclusion Our results demonstrate the important role of microglia in limiting the growth of Aβ plaques and plaque-associated disruption of neuronal connection.

Environmental distresses occurring during the sensitive periods of early life may exacerbate the vulnerability to develop physical and mental diseases in old age. Studies have shown the impact of prenatal stress (PS) on the endocrine development and reprogramming of hypothalamic-pituitary-adrenal axis functions in association with cognitive development and susceptibility to neuropsychiatric diseases. Long-term exposure to glucocorticoids can damage the brain and intensify the progression of Alzheimer's disease (AD)-like neuropathological changes, especially in females. There is, however, less information as to the link between PS and the risk of developing AD pathology throughout the lifespan. In the present study, male and female APP NL-G-F/NL-G-F offspring of dams exposed to gestational noise stress were compared with the control offspring in corticosterone alternations, cognitive and motor performances, and the onset age and development of amyloid beta (Aβ) plaques across age. The hyperactivity of the hypothalamic-pituitary-adrenal axis, spatial learning, and Aβ development were sex specific, showing persistent high levels of stress and further memory loss in females than males, especially in PS mice. The Aβ deposition was started earlier, by 2–3 months, and exhibited a heightened progression in PS animals. The PS also created a long-lasting anxiety-like behavior and impairment in cognitive function and motor coordination. Our results suggested PS as a risk to exacerbate AD-like neuropathological changes during the lifespan, with higher susceptibility of females. The findings were discussed in line with the most likely mechanisms for the PS effects, that is, dysregulation of the neuroendocrine system and the placenta by the PS. • Prenatal stress (PS) resulted in a persistent HPA-axis hyperactivity across age. • The PS created an enduring anxiety-like behavior and impairment in cognitive and motor performances. • The PS led to an earlier onset and overproduction of the Aβ plaques. • The PS was sex-specific in HPA-axis activity, learning function, and Aβ burden. • Females displayed higher susceptibility for developing Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Reduced cerebral blood flow in Alzheimer's disease (AD) may occur in early AD, which contributes to the pathogenesis and/or pathological progression of AD. Reversing this deficit may have therapeutic potential. Certain traditional Chinese herbal medicines (e.g., Saponin and its major component Xueshuantong [XST]) increase blood flow in humans, but whether they could be effective in treating AD patients has not been tested. We found that systemic XST injection elevated cerebral blood flow in APP/PS1 transgenic mice using two-photon time-lapse imaging in the same microvessels before and after injection. Subchronic XST treatment led to improved spatial learning and memory and motor performance in the APP/PS1 mice, suggesting improved neural plasticity and functions. Two-photon time lapse imaging of the same plaques revealed a reduction in plaque size after XST treatment. In addition, western blots experiments showed that XST treatment led to reduced processing of amyloid-β protein precursor (AβPP) and enhanced clearance of amyloid-β (Aβ) without altering the total level of AβPP. We also found increased synapse density in the immediate vicinity of amyloid plaques, suggesting enhanced synaptic function. We conclude that targeting cerebral blood flow can be an effective strategy in treating AD. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease is a neurodegenerative disease that affects many patients worldwide. The amyloid cascade hypothesis has been adopted by most researchers as the mechanism underlying Alzheimer’s disease. Aβ plaques have been considered the core factor in the neurotoxic effect in Alzheimer’s disease, though some controversy remains. Further effort is necessary to elucidate the mechanism and to develop effective treatments. Previous studies have indicated that eliminating Aβ plaques could improve synaptic plasticity and cognitive function. Researchers have developed various forms of vaccines to prevent Aβ deposition or eliminate Aβ plaques and have made some progress. We developed a new vaccine, Aβ3-10-KLH, to increase the level of the anti-Aβ immune response, and we show that this vaccine resulted in a sustained prevention of Aβ deposition at 4 months after cessation of the vaccine treatment. At the same time point, the expression of synaptophysin and NMDAR2B in APP/PS1 transgenic mice was increased by immunization. [ABSTRACT FROM AUTHOR]

Formation and accumulation of amyloid-beta (Aβ) plaques are associated with declined memory and other neurocognitive function in Alzheimer’s disease (AD) patients. However, the effects of Aβ plaques on neural progenitor cells (NPCs) and neurogenesis from NPCs remain largely unknown. The existing data on neurogenesis in AD patients and AD-like animal models remain controversial. For this reason, we utilized the nestin second-intron enhancer controlled LacZ (pNes-LacZ) reporter transgenic mice (pNes-Tg) and Bi-transgenic mice (Bi-Tg) containing both pPDGF-APPSw,Ind and pNes-LacZ transgenes to investigate the effects of Aβ plaques on neurogenesis in the hippocampus and other brain regions of the AD-like mice. We chose transgenic mice at 2, 8 and 12 months of age, corresponding to the stages of Aβ plaque free, plaque onset and plaque progression to analyze the effects of Aβ plaques on the distribution and de novo neurogenesis of (from) NPCs. We demonstrated a slight increase in the number of NPCs in the hippocampal regions at the Aβ plaque free stage, while a significant decrease in the number of NPCs at Aβ plaque onset and progression stages. On the other hand, we showed that Aβ plaques increase neurogenesis, but not gliogenesis from post-mitotic NPCs in the hippocampus of Bi-Tg mice compared with age-matched control pNes-Tg mice. The neurogenic responses of NPCs to Aβ plaques suggest that experimental approaches to promote de novo neurogenesis may potentially improve neurocognitive function and provide an effective therapy for AD.

The pathology of Alzheimer's disease (AD) is featured with extracellular amyloid-β (Aβ) plaques, whose impact on the mechanical properties of the surrounding brain tissues is unclear. Microglia sense and integrate biochemical cues of the microenvironment. However, whether the microglial mechanosensing pathways influence AD pathogenesis is unknown. Here, we surveyed the elevated stiffness of Aβ-plaque-associated tissues and observed the selective upregulation of the mechanosensitive ion channel Piezo1 in Aβ-plaque-associated microglia. Piezo1 sensed the stiffness stimuli of Aβ fibrils and subsequently induced Ca2+ influx for microglial clustering, phagocytosis, and compacting of Aβ plaques. Microglia lacking Piezo1 led to the exacerbation of Aβ pathology and cognitive decline, whereas pharmacological activation of microglial Piezo1 ameliorated brain Aβ burden and cognitive impairment in 5 × FAD mice. Together, our results reveal that Piezo1, a mechanosensor of Aβ fibril stiffness in microglia, represents a potential therapeutic target for AD. [Display omitted] • Aβ plaque-associated tissues become rigid • Microglial Piezo1 senses stiffness of Aβ fibrils • Piezo1 facilitates microglial clearance of Aβ plaques • Pharmaceutical activation of microglial Piezo1 ameliorates brain Aβ burden Hu et al. identify that microglia sense Aβ fibril stiffness through the mechanosensory ion channel Piezo1, which regulates microglial response to Aβ plaques and limits Alzheimer's disease (AD)-like pathology in AD mice, which highlights a protective role of microglial mechanobiology in AD pathogenesis. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) and related dementias show increasing clinical prevalence, yet our understanding of the etiology and pathobiology of disease-related neurodegeneration remains limited. In this regard, noninvasive imaging with radiotracers for positron emission tomography (PET) presents a unique tool for quantifying spatial and temporal changes in characteristic biological markers of brain disease and for assessing potential drug efficacy. PET radiotracers targeting different protein markers are being developed to address questions pertaining to the molecular and/or genetic heterogeneity of AD and related dementias. For example, radiotracers including [11C]-PiB and [18F]-AV-45 (Florbetapir) are being used to measure the density of Aβ-plaques in AD patients and to interrogate the biological mechanisms of disease initiation and progression. Our focus is on the development of novel PET imaging agents, targeting proteins beyond Aβ-plaques, which can be used to investigate the broader mechanism of AD pathogenesis. Here, we present the chemical basis of various radiotracers which show promise in preclinical or clinical studies for use in evaluating the phenotypic or biochemical characteristics of AD. Radiotracers for PET imaging neuroinflammation, metal ion association with Aβ-plaques, tau protein, cholinergic and cannabinoid receptors, and enzymes including glycogen-synthase kinase-3β and monoamine oxidase B amongst others, and their connection to AD are highlighted. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article presents a study that investigates the quantitative correlations between florbetapir F 18 tissue binding with Aβ aggregation. It states that the study used human autopsy brain tissue to evaluate the correlation between florbetapir F 18 binding and Aβ density measured using neuropathologic method. It notes that the result supported the use of florbetapir F 18 as an amyloid positron emission tomography (PET) ligand to identify the presence of Alzheimer disease pathology.

Professor Jellinger first identified that striatal Aβ deposition at postmortem seemed to differentiate cases of dementia with Lewy bodies (DLB) from those with Parkinson's disease dementia (PDD), a finding subsequently questioned. Our replication study in 34 prospectively studied cases assessed the ability of striatal Aβ deposition to differentiate DLB from PDD, and also assessed the relationship between striatal and cortical Aβ deposition and α-synuclein-immunoreactive pathologies, using previously published protocols. Cases with DLB had significantly shorter durations and greater dementia severities compared with cases with PDD. Striatal Aβ-immunoreactive plaques were only consistently found in cases with DLB and correlated with both the severity (positive correlation) and duration (negative correlation) of dementia. Striatal Aβ-immunoreactive plaques also positively correlated with the severity of α-synuclein-immunoreactive pathologies as well as cortical Aβ-positive plaques. Striatal Aβ deposition positively predicted dementia in Lewy body cases with high specificity and had the greatest sensitivity to differentiate DLB from PDD with 100% negative predictive value. These data suggest that striatal Aβ deposition in Lewy body diseases contributes to early dementia and in these cases may impact on the efficacy of treatments targeting the striatum. [ABSTRACT FROM AUTHOR]

APPswe+PS1/ΔE9 transgenic (Tg) mice with Aβ plaque formation in neocortex and hippocampus were evaluated in tests measuring exploratory activity, anxiety, and memory ability using open field test (OFT), Y-maze, contextual fear conditioning (CFC), and Morris water maze (MWM). Wild type (WT) and Tg mice over eight months old showed same locomotion activity and anxiety level in novel stimulation, open field, and Y-maze contexts. In other experiments that measured associative memory and spatial memory in Tg mice and their littermates, the subjects also presented similar deficiencies in memory acquisition. These two aged groups showed abnormal freezing level variance especially in CFC test. In comparison to that in non-transgenic 8-week-old mice group, the acquisition of spatial memory in MWM task was impaired in aged WT and bigenic Tg mice. Taken together, aged wild-type littermates and Tg mice present similar deficits in associative learning and spatial memory independent of amyloid plaques. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a risk factor for the development of Alzheimer''s disease (AD). This immunohistochemical study determined the extent of AD-related changes in temporal cortex resected from individuals treated surgically for severe TBI. Antisera generated against Aβ species (total Aβ, Aβ1–42, and Aβ1–40), the C-terminal of the Aβ precursor protein (APP), apolipoprotein E (apoE), and markers of neuron structure and degeneration (tau, ubiquitin, α-, β-, and γ-synuclein) were used to examine the extent of Aβ plaque deposition and neurodegenerative changes in 18 TBI subjects (ages 18–64 years). Diffuse cortical Aβ deposits were observed in one third of subjects (aged 35–62 years) as early as 2 h after injury, with only one (35-year old) individual exhibiting “mature”, dense-cored plaques. Plaque-like deposits, neurons, glia, and axonal changes were also immunostained with APP and apoE antibodies. In plaque-positive cases, the only statistically significant change in cellular immunostaining was increased neuronal APP (P = 0.013). There was no significant correlation between the distribution of Aβ plaques and markers of neuronal degeneration. Diffuse tau immunostaining was localized to neuronal cell soma, axons or glial cells in a larger subset of individuals. Tau-positive, neurofibrillary tangle (NFT)-like changes were detected in only two subjects, both of more advanced age and who were without Aβ deposits. Other neurodegenerative changes, evidenced by ubiquitin- and synuclein-immunoreactive neurons, were abundant in the majority of cases. Our results demonstrate a differential distribution and course of intra- and extra-cellular AD-like changes during the acute phase following severe TBI in humans. Aβ plaques and early evidence of neuronal degenerative changes can develop rapidly after TBI, while fully developed NFTs most likely result from more chronic disease- or injury-related processes. These observations lend further support to the hypothesis that head trauma significantly increases the risk of developing pathological and clinical symptoms of AD, and provide insight into the molecular mechanisms that initiate these pathological cascades very early during severe brain injury. [Copyright &y& Elsevier]

Besides well-known risk factors for Alzheimer's disease (AD), stress, and in particular noise stress (NS), is a lifestyle risk factor common today. It is known that females are at a significantly greater risk of developing AD than males, and given that stress is a common adversity in females during pregnancy, we hypothesized that gestational noise exposure could exacerbate the postpartum development of the AD-like neuropathological changes during the life span. Pregnant APPNL-G-F/NL-G-F mice were randomly assigned to either the stress condition or control group. The stress group was exposed to the NS on gestational days 12-16, which resulted in a markedly higher hypothalamic-pituitary-adrenal (HPA) axis responsivity during the postpartum stage. Higher amyloid-β (Aβ) deposition and larger Aβ plaque size in the olfactory area were the early onset impacts of the gestational stress (GS) seen at the age of 4 months. This pattern of increased Aβ aggregation and larger plaque size were observed in various brain areas involved in both AD and stress regulation, especially in limbic structures, at the age of 6 months. The GS also produced anxiety-like behavior, deficits in learning and memory, and impaired motor coordination. The findings suggest that environmental stresses during pregnancy pose a potential risk factor in accelerating postpartum cognitive decline and AD-like neuropathological changes in the dams (mothers) later in life., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Amyloid-β (Aβ) accumulation plays a critical role in the pathogenesis of Alzheimer's disease (AD) lesions. Deficiency of Serotonin signaling recently has been linked to the increased Aβ level in transgenic mice and humans. In addition, tryptophan hydroxylase-2 (Tph2), a second tryptophan hydroxylase isoform, controls brain serotonin synthesis. However, it remains to be determined that whether Tph2 deficient APP/PS1mice affect the formation of Aβ plaques in vivo., Methods: Both quantitative and qualitative immunochemistry methods, as well as Congo red staining were used to evaluate the Aβ load and astrogliosis in these animals., Results: we studied alterations of cortex and hippocampus in astrocytes and senile plaques by Tph2 conditional knockout (Tph2 CKO) AD mice from 6-10 months of age. Using Congo red staining and immunostained with Aβ antibody, we showed that plaques load or plaques numbers significantly increased in Tph2 CKO experimental groups at 8 to 10 months old, compared to wild type (WT) group, respectively. Using GFAP+ astrocytes immunofluorescence method, we found that the density of GFAP+ astrocytes markedly enhanced in Tph2 CKO at 10 months. We showed Aβ plaques co-localized autophagic markers LC3 and p62. Nevertheless, we did not observe any co-localization between GFAP+ astrocytes and autophagic markers, but detected the co-localization between βIII-tubulin+ neurons and autophagic markers., Conclusion: Overall, our work provides the preliminary evidence in vivo that Tph2 plays a role in amyloid plaques generation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Alzheimer's disease (AD) is one type of neurodegenerative diseases, which is prevalent in the elderly. Beta-amyloid (Aβ) plaques and phosphorylated tau-induced neurofibrillary tangles are two pathological hallmarks of this disease and the corresponding pathological pathways of these hallmarks are considered as the therapeutic targets. There are many drugs scheduled for pre-clinical and clinical trial that target to inhibit the initiators of pathological Aβ and tau aggregates as well as critical Aβ secretases and kinases in tau hyperphosphorylation. In addition, studies in disease gene variations, and detection of key prognostic effectors in early development are also important for AD control. The discovery of potential drug targets contributed to targeted therapy in a stage-dependent manner, However, there are still some issues that cause concern such as the low bioavailability and low efficacy of candidate drugs from clinical trial reports. Therefore, modification of drug candidates and development of delivery agents are essential and critical. With other medical advancements like cell replacement therapy, there is hope for the cure of Alzheimer's disease in the foreseeable future., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The highly rigid and planar scaffold with π-conjugated systems has been widely considered to be indispensable for Aβ binding probes. However, the flexible benzyloxybenzene derivative [(125)I]BOB-4 represents an excellent lead candidate for targeting Aβ in AD brains. Based on that, we designed two pairs of more flexible and optically pure diphenoxy derivatives with a chiral center as novel Aβ probes. These compounds possessed high affinity (Ki = 15.8-45.0 nM) for Aβ1-42 aggregates, and (R)-enantiomers showed slightly better binding ability than (S)-enantiomers. In addition, the competition binding assay implied that the optically pure diphenoxy derivatives with more flexible geometry shared the same binding site as IMPY, a classical rigid and planar Aβ probe. For (125)I-radiolabeled enantiomers, (S)-[(125)I]5 and (R)-[(125)I]5, specific plaque labeling on brain sections of Tg mice and AD patients were observed in in vitro autoradiography, persuasively proving the excellent affinity of the probes. In biodistribution, (S)-[(125)I]5 and (R)-[(125)I]5 with relatively low lipophilicity exhibited moderate initial brain uptake (4.37% and 3.72% ID/g at 2 min, respectively) and extremely fast washout from normal mice brain (brain2min/brain60min = 19.0 and 17.7, respectively). In summary, the separate enantiomers displayed similar properties in vitro and in vivo, and (S/R)-[(123)I]5 may be potential SPECT probes for recognizing Aβ plaques in AD brains.

Abstract: Noninvasive monitoring of β-amyloid (Aβ) plaques, the neuropathological hallmarks of Alzheimer''s disease (AD), is critical for AD diagnosis and prognosis. Current visualization of Aβ plaques in brains of live patients and animal models is limited in specificity and resolution. The retina as an extension of the brain presents an appealing target for a live, noninvasive optical imaging of AD if disease pathology is manifested there. We identified retinal Aβ plaques in postmortem eyes from AD patients (n =8) and in suspected early stage cases (n =5), consistent with brain pathology and clinical reports; plaques were undetectable in age-matched non-AD individuals (n =5). In APPSWE/PS1∆E9 transgenic mice (AD-Tg; n =18) but not in non-Tg wt mice (n =10), retinal Aβ plaques were detected following systemic administration of curcumin, a safe plaque-labeling fluorochrome. Moreover, retinal plaques were detectable earlier than in the brain and accumulated with disease progression. An immune-based therapy effective in reducing brain plaques, significantly reduced retinal Aβ plaque burden in immunized versus non-immunized AD mice (n =4 mice per group). In live AD-Tg mice (n =24), systemic administration of curcumin allowed noninvasive optical imaging of retinal Aβ plaques in vivo with high resolution and specificity; plaques were undetectable in non-Tg wt mice (n =11). Our discovery of Aβ specific plaques in retinas from AD patients, and the ability to noninvasively detect individual retinal plaques in live AD mice establish the basis for developing high-resolution optical imaging for early AD diagnosis, prognosis assessment and response to therapies. [Copyright &y& Elsevier]