The shared links between Alzheimer’s disease and type 2 diabetes mellitus:Alzheimer’s disease(AD)and type 2 diabetes mellitus(T2DM)are two prevalent conditions that come with substantial daily struggles.Emerging evi...The shared links between Alzheimer’s disease and type 2 diabetes mellitus:Alzheimer’s disease(AD)and type 2 diabetes mellitus(T2DM)are two prevalent conditions that come with substantial daily struggles.Emerging evidence highlights that these diseases share similar pathophysiological features,including insulin resistance and chronic inflammation,which contribute to their rapid progression(Chen et al.,2022).Insulin resistance,a hallmark of T2DM,has been suggested to exacerbate neurodegeneration in AD.Similarly,chronic low-grade inflammation in T2DM parallels with neuroinflammation,which is observed in AD,suggesting overlapping pathophysiological mechanisms in T2DM and AD.展开更多
Alzheimer’s disease is the most common cause of dementia.Although increasing evidence suggests that disruptions in lipid metabolism are closely associated with the disease,the overall profile of lipid and sterol chan...Alzheimer’s disease is the most common cause of dementia.Although increasing evidence suggests that disruptions in lipid metabolism are closely associated with the disease,the overall profile of lipid and sterol changes that occur in the brain during Alzheimer’s disease remains unclear.In this study,we compared brain tissues extracted from 32-week-old male wild-type mice and 5×FAD transgenic Alzheimer’s disease model mice,which carry mutations in the amyloid precursor protein(APP)and presenilin 1(PS1)genes.Using untargeted lipidomics and sterolomics techniques,we investigated the metabolic profiles of lipids,with a focus on sterols specifically,in three brain regions:cerebellum,hippocampus,and olfactory bulb.Our results revealed significant alterations in various lipids,particularly in the hippocampus and olfactory bulb,suggesting changes in energy levels in these regions.Further pathway analysis indicated notable disruptions in key metabolic processes,particularly those related to fatty acids and cell membrane components.Additionally,we observed decreased expression of 15 genes involved in lipid and sterol regulation.Collectively,these findings provide new insights into how imbalances in lipid and sterol metabolism may contribute to the progression of Alzheimer’s disease,highlighting potential metabolic pathways involved in the development of this debilitating disease.展开更多
Neuroinflammation is a crucial factor in the progression of various diseases,ranging from immune-related conditions such as sepsis to neurodegenerative disorders such as Alzheimer’s disease(AD)(Ravichandran and Henek...Neuroinflammation is a crucial factor in the progression of various diseases,ranging from immune-related conditions such as sepsis to neurodegenerative disorders such as Alzheimer’s disease(AD)(Ravichandran and Heneka,2024).This perspective article,which draws on insights from diverse fields including neuroscience,immunology,and pathology,p rovides a critical analysis of ongoing research efforts in inflammasome biology,with specific emphasis on Nod-like receptor(NLR)and pyrin domain-containing protein 3(NLRP3).展开更多
Alzheimer’s disease(AD)remains an incurable neurodegenerative disorder with devastating societal and personal impacts.Despite decades of intensive research,therapeutic efforts targeting the clinical stages of AD have...Alzheimer’s disease(AD)remains an incurable neurodegenerative disorder with devastating societal and personal impacts.Despite decades of intensive research,therapeutic efforts targeting the clinical stages of AD have largely failed to halt or reverse disease progression.This has prompted a critical shift in focus toward the earlier,preclinical stages of AD,where interventions may hold greater promise for altering the disease trajectory.展开更多
Alzheimer’s disease(AD)is the most common form of dementia characterized pathologically by the deposition of amyloid plaques and hyperphosphorylated tau containing neurofibrillary tangles.The disease presents clinica...Alzheimer’s disease(AD)is the most common form of dementia characterized pathologically by the deposition of amyloid plaques and hyperphosphorylated tau containing neurofibrillary tangles.The disease presents clinically with progressive memory loss and disruption of cognitive function.Currently,there is no cure for AD;recent advances in the therapeutics aimed at clearing the amyloid protein from the brain have led to potential disease stabilization,however,this does not prevent eventual disease progression(Cummings et al.,2024).展开更多
Alzheimer’s disease(AD)is a complex,progressive neurodegenerative disorder and the leading cause of dementia worldwide.It is characterized by the accumulation of extracellular amyloid-beta(Aβ)plaques and intracellul...Alzheimer’s disease(AD)is a complex,progressive neurodegenerative disorder and the leading cause of dementia worldwide.It is characterized by the accumulation of extracellular amyloid-beta(Aβ)plaques and intracellular tau neurofibrillary tangles,leading to synaptic dysfunction,neuronal loss,and cognitive decline.These pathological changes can begin decades before clinical symptoms emerge,highlighting the critical need for early,accessible,and accurate diagnostic tools.展开更多
Higher prevalence of sporadic Alzheimer’s disease in women:Alzheimer’s disease(AD)is a progressive neurodegenerative disorder caused by the accumulation of amyloid-β(Aβ)plaques and Tau neurofibrillary tangles in t...Higher prevalence of sporadic Alzheimer’s disease in women:Alzheimer’s disease(AD)is a progressive neurodegenerative disorder caused by the accumulation of amyloid-β(Aβ)plaques and Tau neurofibrillary tangles in the affected brain regions.The clearance of these pathological protein aggregates by microglia can trigger excessive neuroinflammation,which contributes to brain atrophy.AD exhibits clinical heterogeneity and is characterized by highly complex,multifactorial etiology(Lopez-Lee et al.,2024).展开更多
Alzheimer’s disease(AD)is the most common form of dementia.In addition to the lack of effective treatments,there are limitations in diagnostic capabilities.The complexity of AD itself,together with a variety of other...Alzheimer’s disease(AD)is the most common form of dementia.In addition to the lack of effective treatments,there are limitations in diagnostic capabilities.The complexity of AD itself,together with a variety of other diseases often observed in a patient’s history in addition to their AD diagnosis,make deciphering the molecular mechanisms that underlie AD,even more important.Large datasets of single-cell RNA sequencing,single-nucleus RNA-sequencing(snRNA-seq),and spatial transcriptomics(ST)have become essential in guiding and supporting new investigations into the cellular and regional susceptibility of AD.However,with unique technology,software,and larger databases emerging;a lack of integration of these data can contribute to ineffective use of valuable knowledge.Importantly,there was no specialized database that concentrates on ST in AD that offers comprehensive differential analyses under various conditions,such as sex-specific,region-specific,and comparisons between AD and control groups until the new Single-cell and Spatial RNA-seq databasE for Alzheimer’s Disease(ssREAD)database(Wang et al.,2024)was introduced to meet the scientific community’s growing demand for comprehensive,integrated,and accessible data analysis.展开更多
Alzheimer’s disease(AD)is the most common cause of dementia,characterized by progressive cognitive decline,and affects over 55 million people worldwide.AD is pathological featured by the aberrant accumulation of amyl...Alzheimer’s disease(AD)is the most common cause of dementia,characterized by progressive cognitive decline,and affects over 55 million people worldwide.AD is pathological featured by the aberrant accumulation of amyloid-βplaques,neurofibrillary tangles formed by hyperphosphorylated tau,synaptic loss,and dysfunction of neurotransmitter systems.Evidence from in vivo and autopsy studies has consistently shown that synaptic dysfunction and loss are strongly correlated with cognitive decline in AD,particularly in brain regions such as the hippocampus and cortex,which are critical for memory formation and processing.This perspective highlights recent histopathological findings related to synaptic dysfunction in AD,advancements in the development of imaging and fluid-based biomarkers for synaptic loss,and future studies.展开更多
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most prominent cause of dementia.In 2019,over 57.4million people were living with AD and other dementia subtypes,a number which is ex...Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most prominent cause of dementia.In 2019,over 57.4million people were living with AD and other dementia subtypes,a number which is expected to increase to over 152.8 million in the next 25years.This ever-increasing burden has resulted in AD and other neurodegenerative diseases rising to one of the top 10 causes of death globally (O'Connell et al.,2024).展开更多
Advances in Alzheimer's disease(AD)research have deepened our understanding,yet the mechanisms driving its progression remain unclear.Although a range of in vivo biomarkers is now available(e.g.,measurements of am...Advances in Alzheimer's disease(AD)research have deepened our understanding,yet the mechanisms driving its progression remain unclear.Although a range of in vivo biomarkers is now available(e.g.,measurements of amyloidbeta(Aβ)and ta u accumulation-the molecular hallmarks of AD-structural magnetic resonance imaging(MRI),assessments of brain metabolism,and,more recently,blood-based markers),a definitive diagnosis of AD continues to be challenging.For example,Frisoni et al.展开更多
Alzheimer’s disease is a multi-amyloidosis disease characterized by amyloid-βdeposits in brain blood vessels,microaneurysms,and senile plaques.How amyloid-βdeposition affects axon pathology has not been examined ex...Alzheimer’s disease is a multi-amyloidosis disease characterized by amyloid-βdeposits in brain blood vessels,microaneurysms,and senile plaques.How amyloid-βdeposition affects axon pathology has not been examined extensively.We used immunohistochemistry and immunofluorescence staining to analyze the forebrain tissue slices of Alzheimer’s disease patients.Widespread axonal amyloidosis with distinctive axonal enlargement was observed in patients with Alzheimer’s disease.On average,amyloid-β-positive axon diameters in Alzheimer’s disease brains were 1.72 times those of control brain axons.Furthermore,axonal amyloidosis was associated with microtubule-associated protein 2 reduction,tau phosphorylation,lysosome destabilization,and several blood-related markers,such as apolipoprotein E,alpha-hemoglobin,glycosylated hemoglobin type A1C,and hemin.Lysosome destabilization in Alzheimer’s disease was also clearly identified in the neuronal soma,where it was associated with the co-expression of amyloid-β,Cathepsin D,alpha-hemoglobin,actin alpha 2,and collagen type IV.This suggests that exogenous hemorrhagic protein intake influences neural lysosome stability.Additionally,the data showed that amyloid-β-containing lysosomes were 2.23 times larger than control lysosomes.Furthermore,under rare conditions,axonal breakages were observed,which likely resulted in Wallerian degeneration.In summary,axonal enlargement associated with amyloidosis,micro-bleeding,and lysosome destabilization is a major defect in patients with Alzheimer’s disease.This finding suggests that,in addition to the well-documented neural soma and synaptic damage,axonal damage is a key component of neuronal defects in Alzheimer’s disease.展开更多
Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the...Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.展开更多
MicroRNAs(miRNAs),small non-coding RNAs ranging from 19 to 25 nucleotides in length,are key regulators of gene expression that function primarily by inhibiting the translation of target mRNAs.Recent studies have sugge...MicroRNAs(miRNAs),small non-coding RNAs ranging from 19 to 25 nucleotides in length,are key regulators of gene expression that function primarily by inhibiting the translation of target mRNAs.Recent studies have suggested that miRNAs play important roles in regulating key aspects in the pathology of Alzheimer's disease,including the modulation and accumulation of amyloid-beta and tau proteins.Moreover,miRNAs have been implicated in the regulation of neuroinflammation thro ugh various inflammatory pathways,notably the nuclear factor kappa B signaling cascade.Additional emerging evidence has shown that miRNAs regulate synaptic growth and maturation,and they perform promising roles in regulating neuronal death and development.miRNAs also offer a novel avenue for direct reprogramming of neurons,representing a promising strategy for Alzheimer's disease treatment.The regulation of miRNA biogenesis and the post-transcriptional modifications of miRNAs are critical factors in Alzheimer's disease pathology,influencing miRNA activity and disease progression.In this review,we comprehensively explore the role of different miRNAs in regulating various pathological processes associated with Alzheimer's disease,focusing primarily on four representative miRNAs:miR-9,miR-29,miR-126,and miR-146a for further exploration.We also discuss the influence of miRNA biogenesis on Alzheimer's disease,emphasizing how dysregulation of miRNA processing may contribute to the disease.Additionally,we highlight the potential of miRNAs as both diagnostic biomarke rs and therapeutic targets in Alzheimer's disease,along with promising vector delive ry strategies aimed at improving clinical outcomes.Finally,we discuss the challenges and limitations associated with the use of miRNAs in the diagnosis and treatment of Alzheimer's disease.By reviewing the current clinical applications of miRNAs as biomarkers and therapeutic agents,we aim to provide insights that will inform future research and development in this promising field.展开更多
Alzheimer s disease is a progressive neurodegenerative disease chara cterized by memory decline and the accumulation of abnormal protein aggregates in the brain.While the precise cause of Alzheimer s disease remains u...Alzheimer s disease is a progressive neurodegenerative disease chara cterized by memory decline and the accumulation of abnormal protein aggregates in the brain.While the precise cause of Alzheimer s disease remains under investigation,recent research suggests that dys regulation of brainspecific microRNAs(miRs)plays a significant role in Alzheimer s disease pathogenesis.Brain-specific miRs are predominantly expressed within the central nervous system and are crucial for neuronal development,and function,potentially in brain disorders.This review identifies some key brainspecific miRs in Alzheimer's disease,including miR-9,miR-26b,miR-34a,miR-107,miR-124,miR-125b,miR-128,miR-132,miR-146a,miR-155,miR-219,miR-501-3p,and miR-502-3p.The review also shed light on the brain-specific location of these miRs,their dysregulation in Alzheimer s disease,and how they are involved in disease progression.Apparently,these brain-specific miRs modulate specific genes and are therefo re crucial for various cellular processes,including autophagy,cell cycle,tau phosphorylation,amyloid-beta production,and neuroinflammation.Moreover,these miRs are potent disease-modifying factors and their expression levels co uld serve as potential biomarkers for diagnosing or monitoring Alzheimer s disease progression.展开更多
Alzheimer’s disease(AD)is the most common form of dementia,affecting over 50 million people worldwide.This figure is projected to nearly double every 20 years,reaching 82 million by 2030 and 152 million by 2050(Alzhe...Alzheimer’s disease(AD)is the most common form of dementia,affecting over 50 million people worldwide.This figure is projected to nearly double every 20 years,reaching 82 million by 2030 and 152 million by 2050(Alzheimer’s Disease International).The apolipoproteinε4(APOE4)allele is the strongest genetic risk factor for late-onset AD(after age 65 years).Apolipoprotein E,a lipid transporter,exists in three variants:ε2,ε3,andε4.APOEε2(APOE2)is protective against AD,APOEε3(APOE3)is neutral,while APOE4 significantly increases the risk.Individuals with one copy of APOE4 have a 4-fold greater risk of developing AD,and those with two copies face an 8-fold risk compared to non-carriers.Even in cognitively normal individuals,APOE4 carriers exhibit brain metabolic and vascular deficits decades before amyloid-beta(Aβ)plaques and neurofibrillary tau tangles emerge-the hallmark pathologies of AD(Reiman et al.,2001,2005;Thambisetty et al.,2010).Notably,studies have demonstrated reduced glucose uptake,or hypometabolism,in brain regions vulnerable to AD in asymptomatic middle-aged APOE4 carriers,long before clinical symptoms arise(Reiman et al.,2001,2005).展开更多
Traditional clinical subtype classifications(such as amnestic and non-amnestic mild cognitive impairment)rely on subjective interpretations of overlapping patterns of performance on cognitive tests,which may lead to u...Traditional clinical subtype classifications(such as amnestic and non-amnestic mild cognitive impairment)rely on subjective interpretations of overlapping patterns of performance on cognitive tests,which may lead to unreliable categorization.A more precise and objective classification of mild cognitive impairment subtypes can be achieved through data-driven clustering techniques.However,because previous studies have not restricted their cohorts to patients who have mild cognitive impairment with the pathology of Alzheimer’s disease,the nature of cognitive variability and its impact on disease progression in a strictly defined biomarker-positive preclinical Alzheimer’s disease cohort remains unknown.We examined cognitive heterogeneity among participants with mild cognitive impairment due to Alzheimer’s disease and evaluated its prognostic utility.Neuropsychological test data from 389 patients with mild cognitive impairment in whom the cerebrospinal fluid biomarker confirmed Alzheimer’s disease were obtained from the Alzheimer’s Disease Neuroimaging Initiative cohorts.Principal component analysis and model-based clustering were used to identify cognitive profiles,which were then validated through a 100-time bootstrap analysis.Pairwise comparisons tested for differences between the identified subgroups in participant characteristics,scores on cognitive and clinical outcomes,levels of cerebrospinal fluid biomarkers,and magnetic resonance imaging-derived brain volumes.Longitudinal analyses evaluated differences in rate of change of magnetic resonance imaging volumetric measurements and clinical outcomes over 48 months.Survival analysis assessed risk for conversion to dementia.Alpha-synuclein levels and white matter hyperintensity volumes were considered for sensitivity analysis.Two distinct cognitive profiles were identified:a“typical”group(56.04%of the sample)that demonstrated relatively poorer scores on memory testing than non-memory tests,and an“atypical”group(43.96%of the sample)with smaller differences between memory and non-memory measures,indicating a more uniform pattern of impairment across cognitive domains.While the groups had comparable levels of overall cognitive impairment and cerebrospinal fluid biomarkers of Alzheimer’s disease,the typical group displayed accelerated atrophy rates every 6 months across multiple brain regions(hippocampus:29.02 mm^(3),standard error[SE]=10.13,P=0.005;whole brain:1799.85 mm^(3),SE=781.57,P=0.023;entorhinal cortex:22.26 mm^(3),SE=11.15,P=0.048;fusiform gyrus:66.24 mm^(3),SE=28.53,P=0.021).Survival analysis revealed markedly higher dementia conversion risk(hazard ratio:1.70,95%confidence interval:1.27,2.27,P<0.001)and shorter progression time in the typical group.These findings persisted after controlling for comorbid pathologies.In conclusion,this data-driven approach identified two distinct cognitive subtypes of mild cognitive impairment due to Alzheimer’s disease that differed in their rates of clinical decline and neurodegeneration.These findings could be used to improve prognostic models and inform clinical trial stratification.展开更多
The increasing prevalence of metabolic disorders and neurodegenerative diseases has uncovered shared pathophysiological pathways,with insulin resistance and mitochondrial dysfunction emerging as critical contributors ...The increasing prevalence of metabolic disorders and neurodegenerative diseases has uncovered shared pathophysiological pathways,with insulin resistance and mitochondrial dysfunction emerging as critical contributors to cognitive decline.Insulin resistance impairs neuronal metabolism and synaptic function,fostering neurodegeneration as observed in Alzheimer’s disease and Down syndrome.Indeed,Down syndrome,characterized by the triplication of the APP gene,represents a valuable genetic model for studying early-onset Alzheimer’s disease and accelerated aging.Building on the link between metabolic dysfunctions and neurodegeneration,innovative strategies addressed brain insulin resistance as a key driver of cognitive decline.Intranasal insulin has shown promise in improving cognition in early Alzheimer’s disease and type 2 diabetes,supporting the concept that restoring insulin sensitivity can mitigate neurodegeneration.However,insulin-based therapies risk desensitizing insulin signaling,potentially worsening the disease.Incretins,particularly glucagon-like peptide 1 receptor agonists,offer neuroprotective benefits by enhancing insulin sensitivity,metabolism,and synaptic plasticity while reducing oxidative distress and neuroinflammation.This review focuses on current knowledge on the metabolic and molecular interactions between insulin resistance,mitochondrial dynamics(including their roles in energy metabolism),and oxidative distress regulation,as these are pivotal in both Alzheimer’s disease and Down syndrome.By addressing these interconnected mechanisms,innovative treatments may emerge for both metabolic and neurodegenerative disorders.展开更多
Alterations in RNA methylation may affect the initiation and development of Alzheimer’s disease.However,the exact nature of the relationship between RNA methylation and Alzheimer’s disease remains unclear.In this st...Alterations in RNA methylation may affect the initiation and development of Alzheimer’s disease.However,the exact nature of the relationship between RNA methylation and Alzheimer’s disease remains unclear.In this study,RNA methylation levels were analyzed by bulk transcriptomic and single-cell RNA sequencing.The expression levels of RNA methylation regulators were confirmed using molecular biology techniques.Co-expression network analysis was used to identify relevant long non-coding RNAs.Molecular subtypes related to RNA methylation were classified,and variations in clinical characteristics,biological behavior,and immune signatures between subtypes were assessed.Machine learning approaches were applied to identify methylation-associated long non-coding RNAs,which were used to construct a risk model and nomogram for Alzheimer’s disease.Potential therapeutic agents for different risk groups were predicted,and in vitro experiments were conducted to identify key RNA methylation events.Single-cell analysis demonstrated enhanced RNA methylation in patients with Alzheimer’s disease,particularly within T cells,B cells,and NK cells.Quantitative reverse transcription-polymerase chain reaction and western blot confirmed alterations in RNA methylation regulators in neurons treated with amyloid-βoligomers in vitro.This evidence supported the classification of patients with Alzheimer’s disease into heterogeneous subtypes.Specifically,subtype 1 was identified as the immune-active subtype,while subtype 2 was characterized by a metabolic phenotype.Machine learning algorithms identified five significant methylation-associated long non-coding RNAs-LINC01007,MAP4K3-DT,MIR302CHG,VAC14-AS1,and TGFB2-OT1-that accurately predict clinical outcomes for patients with Alzheimer’s disease.These patients were classified into low-and high-risk categories;the latter group displayed higher immune infiltration,upregulated immune regulatory gene expression,and elevated immune scores and responded better to treatment with arachidonic-trifluoroethane.These findings suggest that dysregulated RNA methylation alters the immune microenvironment in Alzheimer’s disease and is closely associated with its progression.This phenomenon provides novel insights into potential therapeutic strategies for Alzheimer’s disease that target RNA methylation.展开更多
In Alzheimer’s disease,microglial phagocytosis is engaged in the pathogenesis as it clears abnormal protein accumulations,debris,and apoptotic cells in the early stages of Alzheimer’s disease,but fuels neuroinflamma...In Alzheimer’s disease,microglial phagocytosis is engaged in the pathogenesis as it clears abnormal protein accumulations,debris,and apoptotic cells in the early stages of Alzheimer’s disease,but fuels neuroinflammation and accelerates disease progression in later stages.In vivo parabiosis experiments in aged animals have demonstrated that blood-born factors modulate synaptic plasticity,neurogenesis,and microglial responses.We hypothesize that peripheral factors can modulate microglial function and thereby possibly influence Alzheimer’s disease pathology.The objective of this study is to investigate the effects of Alzheimer’s disease serum on microglial phagocytosis.Here,we use an immortalized human microglial cell line in an in vitro parabiosis assay to investigate the impact of the serum from individuals diagnosed with Alzheimer’s disease(n=30)and age-matched controls(n=30)(PRODEM study)on microglial phagocytosis.Exposure to Alzheimer’s disease serum increased microglial phagocytic uptake of pH-sensitive fluorescent particles and downregulated expression of the lysosomal master regulator transcription factor EB(TFEB)and of ATPase H^(+)transporting lysosomal V1 subunit B2(ATP6V1B2),a component of the vacuolar ATPase.To identify serum components that may relate to changes in phagocytosis,serum samples of the Three-City Study(3C Study)were used.In the 3C Study,blood samples were collected up to 12 years before the onset of cognitive decline or dementia and their serum metabolome is well-defined.Microglia exposed to the serum of future Alzheimer’s disease patients from the 3C Study displayed an increased phagocytic uptake compared with the serum of matched controls,depending on the presence of the apolipoprotein Eε4 allele in the Alzheimer’s disease patients.Furthermore,microglial phagocytosis correlated inversely with serum levels of the omega-3 fatty acid eicosapentaenoic acid.We confirmed this inverse correlation between eicosapentaenoic acid and phagocytosis in the serum samples of the PRODEM cohort.In addition,in vitro testing of eicosapentaenoic acid on microglial phagocytosis showed a concentration-dependent decrease in phagocytic uptake.In conclusion,following incubation with Alzheimer’s disease blood serum,we observed increased microglial phagocytic uptake and the downregulation of TFEB and ATP6V1B2,possibly indicating lysosomal dysfunction.Furthermore,microglial phagocytosis was inversely correlated with serum eicosapentaenoic acid levels,suggesting an important role for dietary eicosapentaenoic acid in microglial function.展开更多
基金supported by grants from NIH T32(DK007260,to WC)the Steno North American Fellowship awarded by the Novo Nordisk Foundation(NNF23OC0087108,to WC).
文摘The shared links between Alzheimer’s disease and type 2 diabetes mellitus:Alzheimer’s disease(AD)and type 2 diabetes mellitus(T2DM)are two prevalent conditions that come with substantial daily struggles.Emerging evidence highlights that these diseases share similar pathophysiological features,including insulin resistance and chronic inflammation,which contribute to their rapid progression(Chen et al.,2022).Insulin resistance,a hallmark of T2DM,has been suggested to exacerbate neurodegeneration in AD.Similarly,chronic low-grade inflammation in T2DM parallels with neuroinflammation,which is observed in AD,suggesting overlapping pathophysiological mechanisms in T2DM and AD.
基金supported by the National Natural Science Foundation of China,Nos.82200784,32271311Qizhen Foundation,No.226‐2023‐00008(all to LH).
文摘Alzheimer’s disease is the most common cause of dementia.Although increasing evidence suggests that disruptions in lipid metabolism are closely associated with the disease,the overall profile of lipid and sterol changes that occur in the brain during Alzheimer’s disease remains unclear.In this study,we compared brain tissues extracted from 32-week-old male wild-type mice and 5×FAD transgenic Alzheimer’s disease model mice,which carry mutations in the amyloid precursor protein(APP)and presenilin 1(PS1)genes.Using untargeted lipidomics and sterolomics techniques,we investigated the metabolic profiles of lipids,with a focus on sterols specifically,in three brain regions:cerebellum,hippocampus,and olfactory bulb.Our results revealed significant alterations in various lipids,particularly in the hippocampus and olfactory bulb,suggesting changes in energy levels in these regions.Further pathway analysis indicated notable disruptions in key metabolic processes,particularly those related to fatty acids and cell membrane components.Additionally,we observed decreased expression of 15 genes involved in lipid and sterol regulation.Collectively,these findings provide new insights into how imbalances in lipid and sterol metabolism may contribute to the progression of Alzheimer’s disease,highlighting potential metabolic pathways involved in the development of this debilitating disease.
基金supported by Texas Alzheimer’s Research and Care Consortium-TARCC 2022-26,The National Football League Players Association-NFLPA,NIH/NIA Grant 1R01 AG072491 to TB and FDP.
文摘Neuroinflammation is a crucial factor in the progression of various diseases,ranging from immune-related conditions such as sepsis to neurodegenerative disorders such as Alzheimer’s disease(AD)(Ravichandran and Heneka,2024).This perspective article,which draws on insights from diverse fields including neuroscience,immunology,and pathology,p rovides a critical analysis of ongoing research efforts in inflammasome biology,with specific emphasis on Nod-like receptor(NLR)and pyrin domain-containing protein 3(NLRP3).
基金supported by the Canadian Institutes of Health Research Project grant (PJT-169197) to QYsupported by a CGS-M fellowship from the Canadian Institutes of Health Research
文摘Alzheimer’s disease(AD)remains an incurable neurodegenerative disorder with devastating societal and personal impacts.Despite decades of intensive research,therapeutic efforts targeting the clinical stages of AD have largely failed to halt or reverse disease progression.This has prompted a critical shift in focus toward the earlier,preclinical stages of AD,where interventions may hold greater promise for altering the disease trajectory.
基金funded by Wellcome 4ward North(Ref:216340/Z/19/Z)ARUK Yorkshire Network Centre Small Grant Scheme,ARUK Preparatory Clinical Fellowship scheme(Ref:ARUK-PCRF2016A-1)+3 种基金Academy of Medical Sciences Starter Grants for Clinical Lecturers Scheme(Ref:SGL028\1097),Parkinson’s UK(Ref:F1301)Michael J Fox Foundation(Ref:005021),Australian Research Council(CE200100012)European Union Seventh Framework Programme(Ref:FP7/2007-2013)under grant agreement no.601055the NIHR Sheffield Biomedical Research Centre award(NIHR 203321)(to SMB).
文摘Alzheimer’s disease(AD)is the most common form of dementia characterized pathologically by the deposition of amyloid plaques and hyperphosphorylated tau containing neurofibrillary tangles.The disease presents clinically with progressive memory loss and disruption of cognitive function.Currently,there is no cure for AD;recent advances in the therapeutics aimed at clearing the amyloid protein from the brain have led to potential disease stabilization,however,this does not prevent eventual disease progression(Cummings et al.,2024).
文摘Alzheimer’s disease(AD)is a complex,progressive neurodegenerative disorder and the leading cause of dementia worldwide.It is characterized by the accumulation of extracellular amyloid-beta(Aβ)plaques and intracellular tau neurofibrillary tangles,leading to synaptic dysfunction,neuronal loss,and cognitive decline.These pathological changes can begin decades before clinical symptoms emerge,highlighting the critical need for early,accessible,and accurate diagnostic tools.
基金supported by Temasek Life Sciences Laboratory core funding(3160)(to CTO).
文摘Higher prevalence of sporadic Alzheimer’s disease in women:Alzheimer’s disease(AD)is a progressive neurodegenerative disorder caused by the accumulation of amyloid-β(Aβ)plaques and Tau neurofibrillary tangles in the affected brain regions.The clearance of these pathological protein aggregates by microglia can trigger excessive neuroinflammation,which contributes to brain atrophy.AD exhibits clinical heterogeneity and is characterized by highly complex,multifactorial etiology(Lopez-Lee et al.,2024).
文摘Alzheimer’s disease(AD)is the most common form of dementia.In addition to the lack of effective treatments,there are limitations in diagnostic capabilities.The complexity of AD itself,together with a variety of other diseases often observed in a patient’s history in addition to their AD diagnosis,make deciphering the molecular mechanisms that underlie AD,even more important.Large datasets of single-cell RNA sequencing,single-nucleus RNA-sequencing(snRNA-seq),and spatial transcriptomics(ST)have become essential in guiding and supporting new investigations into the cellular and regional susceptibility of AD.However,with unique technology,software,and larger databases emerging;a lack of integration of these data can contribute to ineffective use of valuable knowledge.Importantly,there was no specialized database that concentrates on ST in AD that offers comprehensive differential analyses under various conditions,such as sex-specific,region-specific,and comparisons between AD and control groups until the new Single-cell and Spatial RNA-seq databasE for Alzheimer’s Disease(ssREAD)database(Wang et al.,2024)was introduced to meet the scientific community’s growing demand for comprehensive,integrated,and accessible data analysis.
基金supported by Swiss Center for Applied Human Toxicology(SCAHT AP22-01)(to RN).
文摘Alzheimer’s disease(AD)is the most common cause of dementia,characterized by progressive cognitive decline,and affects over 55 million people worldwide.AD is pathological featured by the aberrant accumulation of amyloid-βplaques,neurofibrillary tangles formed by hyperphosphorylated tau,synaptic loss,and dysfunction of neurotransmitter systems.Evidence from in vivo and autopsy studies has consistently shown that synaptic dysfunction and loss are strongly correlated with cognitive decline in AD,particularly in brain regions such as the hippocampus and cortex,which are critical for memory formation and processing.This perspective highlights recent histopathological findings related to synaptic dysfunction in AD,advancements in the development of imaging and fluid-based biomarkers for synaptic loss,and future studies.
文摘Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most prominent cause of dementia.In 2019,over 57.4million people were living with AD and other dementia subtypes,a number which is expected to increase to over 152.8 million in the next 25years.This ever-increasing burden has resulted in AD and other neurodegenerative diseases rising to one of the top 10 causes of death globally (O'Connell et al.,2024).
文摘Advances in Alzheimer's disease(AD)research have deepened our understanding,yet the mechanisms driving its progression remain unclear.Although a range of in vivo biomarkers is now available(e.g.,measurements of amyloidbeta(Aβ)and ta u accumulation-the molecular hallmarks of AD-structural magnetic resonance imaging(MRI),assessments of brain metabolism,and,more recently,blood-based markers),a definitive diagnosis of AD continues to be challenging.For example,Frisoni et al.
基金supported by the National Natural Science Foundation of China,No.81472235(to HF)the Shanghai Jiao Tong University Medical and Engineering Project,Nos.YG2021QN53(to HF),YG2017MS71(to HF)+1 种基金the International Cooperation Project of the National Natural Science Foundation of China,No.82020108017(to DC)the Innovation Group Project of the National Natural Science Foundation of China,No.81921002(to DC).
文摘Alzheimer’s disease is a multi-amyloidosis disease characterized by amyloid-βdeposits in brain blood vessels,microaneurysms,and senile plaques.How amyloid-βdeposition affects axon pathology has not been examined extensively.We used immunohistochemistry and immunofluorescence staining to analyze the forebrain tissue slices of Alzheimer’s disease patients.Widespread axonal amyloidosis with distinctive axonal enlargement was observed in patients with Alzheimer’s disease.On average,amyloid-β-positive axon diameters in Alzheimer’s disease brains were 1.72 times those of control brain axons.Furthermore,axonal amyloidosis was associated with microtubule-associated protein 2 reduction,tau phosphorylation,lysosome destabilization,and several blood-related markers,such as apolipoprotein E,alpha-hemoglobin,glycosylated hemoglobin type A1C,and hemin.Lysosome destabilization in Alzheimer’s disease was also clearly identified in the neuronal soma,where it was associated with the co-expression of amyloid-β,Cathepsin D,alpha-hemoglobin,actin alpha 2,and collagen type IV.This suggests that exogenous hemorrhagic protein intake influences neural lysosome stability.Additionally,the data showed that amyloid-β-containing lysosomes were 2.23 times larger than control lysosomes.Furthermore,under rare conditions,axonal breakages were observed,which likely resulted in Wallerian degeneration.In summary,axonal enlargement associated with amyloidosis,micro-bleeding,and lysosome destabilization is a major defect in patients with Alzheimer’s disease.This finding suggests that,in addition to the well-documented neural soma and synaptic damage,axonal damage is a key component of neuronal defects in Alzheimer’s disease.
基金supported by the Nature Science Foundation of Liaoning Province,Nos.2022-MS-211,2021-MS-064,and 2024-MS-048(all to YC).
文摘Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.
基金National Natural Science Foundation of China,No.82405067(to YW)。
文摘MicroRNAs(miRNAs),small non-coding RNAs ranging from 19 to 25 nucleotides in length,are key regulators of gene expression that function primarily by inhibiting the translation of target mRNAs.Recent studies have suggested that miRNAs play important roles in regulating key aspects in the pathology of Alzheimer's disease,including the modulation and accumulation of amyloid-beta and tau proteins.Moreover,miRNAs have been implicated in the regulation of neuroinflammation thro ugh various inflammatory pathways,notably the nuclear factor kappa B signaling cascade.Additional emerging evidence has shown that miRNAs regulate synaptic growth and maturation,and they perform promising roles in regulating neuronal death and development.miRNAs also offer a novel avenue for direct reprogramming of neurons,representing a promising strategy for Alzheimer's disease treatment.The regulation of miRNA biogenesis and the post-transcriptional modifications of miRNAs are critical factors in Alzheimer's disease pathology,influencing miRNA activity and disease progression.In this review,we comprehensively explore the role of different miRNAs in regulating various pathological processes associated with Alzheimer's disease,focusing primarily on four representative miRNAs:miR-9,miR-29,miR-126,and miR-146a for further exploration.We also discuss the influence of miRNA biogenesis on Alzheimer's disease,emphasizing how dysregulation of miRNA processing may contribute to the disease.Additionally,we highlight the potential of miRNAs as both diagnostic biomarke rs and therapeutic targets in Alzheimer's disease,along with promising vector delive ry strategies aimed at improving clinical outcomes.Finally,we discuss the challenges and limitations associated with the use of miRNAs in the diagnosis and treatment of Alzheimer's disease.By reviewing the current clinical applications of miRNAs as biomarkers and therapeutic agents,we aim to provide insights that will inform future research and development in this promising field.
基金National Institute on Aging(NIA),National Institutes of Health(NIH),Nos.K99AG065645,RO0AG065645,ROOAG065645-04S1SARP mini grants TTUHSC EP,Edward N.&Margaret G.Marsh FoundationTTUHSC EP MTM Startup Funds(all to SK)。
文摘Alzheimer s disease is a progressive neurodegenerative disease chara cterized by memory decline and the accumulation of abnormal protein aggregates in the brain.While the precise cause of Alzheimer s disease remains under investigation,recent research suggests that dys regulation of brainspecific microRNAs(miRs)plays a significant role in Alzheimer s disease pathogenesis.Brain-specific miRs are predominantly expressed within the central nervous system and are crucial for neuronal development,and function,potentially in brain disorders.This review identifies some key brainspecific miRs in Alzheimer's disease,including miR-9,miR-26b,miR-34a,miR-107,miR-124,miR-125b,miR-128,miR-132,miR-146a,miR-155,miR-219,miR-501-3p,and miR-502-3p.The review also shed light on the brain-specific location of these miRs,their dysregulation in Alzheimer s disease,and how they are involved in disease progression.Apparently,these brain-specific miRs modulate specific genes and are therefo re crucial for various cellular processes,including autophagy,cell cycle,tau phosphorylation,amyloid-beta production,and neuroinflammation.Moreover,these miRs are potent disease-modifying factors and their expression levels co uld serve as potential biomarkers for diagnosing or monitoring Alzheimer s disease progression.
基金supported by National Institute on Aging(NIH-NIA)R01AG054459(to ALL).
文摘Alzheimer’s disease(AD)is the most common form of dementia,affecting over 50 million people worldwide.This figure is projected to nearly double every 20 years,reaching 82 million by 2030 and 152 million by 2050(Alzheimer’s Disease International).The apolipoproteinε4(APOE4)allele is the strongest genetic risk factor for late-onset AD(after age 65 years).Apolipoprotein E,a lipid transporter,exists in three variants:ε2,ε3,andε4.APOEε2(APOE2)is protective against AD,APOEε3(APOE3)is neutral,while APOE4 significantly increases the risk.Individuals with one copy of APOE4 have a 4-fold greater risk of developing AD,and those with two copies face an 8-fold risk compared to non-carriers.Even in cognitively normal individuals,APOE4 carriers exhibit brain metabolic and vascular deficits decades before amyloid-beta(Aβ)plaques and neurofibrillary tau tangles emerge-the hallmark pathologies of AD(Reiman et al.,2001,2005;Thambisetty et al.,2010).Notably,studies have demonstrated reduced glucose uptake,or hypometabolism,in brain regions vulnerable to AD in asymptomatic middle-aged APOE4 carriers,long before clinical symptoms arise(Reiman et al.,2001,2005).
基金funded by Shanghai Baiyulan Pujiang Project(No.24PJD087)funded by the National Natural Science Foundation of China(No.12401347)+5 种基金Shanghai“Science and Technology Innovation Action Plan”Computational Biology Key Project(Nos.23JS1400500 and 23JS1400800)Chinese MOE Foundation on Humanities and Social Sciences(No.23YJC910006)the Natural Science Foundation of Shanghai(No.24ZR1420400)MWB was funded by NIH/NIA(Nos.R01AG082073,R01AG079280,and P30AG062429)HHF was funded by NIH/NIA(Nos.U19AG079774-01,R01AG061146,P30AG062429,R01AG076634-01,CIHR 137794)funded by NIH/NIA R01AG064002,P30AG062429,R01AG076634,and the Epstein Family Alzheimer’s Research Collaboration.
文摘Traditional clinical subtype classifications(such as amnestic and non-amnestic mild cognitive impairment)rely on subjective interpretations of overlapping patterns of performance on cognitive tests,which may lead to unreliable categorization.A more precise and objective classification of mild cognitive impairment subtypes can be achieved through data-driven clustering techniques.However,because previous studies have not restricted their cohorts to patients who have mild cognitive impairment with the pathology of Alzheimer’s disease,the nature of cognitive variability and its impact on disease progression in a strictly defined biomarker-positive preclinical Alzheimer’s disease cohort remains unknown.We examined cognitive heterogeneity among participants with mild cognitive impairment due to Alzheimer’s disease and evaluated its prognostic utility.Neuropsychological test data from 389 patients with mild cognitive impairment in whom the cerebrospinal fluid biomarker confirmed Alzheimer’s disease were obtained from the Alzheimer’s Disease Neuroimaging Initiative cohorts.Principal component analysis and model-based clustering were used to identify cognitive profiles,which were then validated through a 100-time bootstrap analysis.Pairwise comparisons tested for differences between the identified subgroups in participant characteristics,scores on cognitive and clinical outcomes,levels of cerebrospinal fluid biomarkers,and magnetic resonance imaging-derived brain volumes.Longitudinal analyses evaluated differences in rate of change of magnetic resonance imaging volumetric measurements and clinical outcomes over 48 months.Survival analysis assessed risk for conversion to dementia.Alpha-synuclein levels and white matter hyperintensity volumes were considered for sensitivity analysis.Two distinct cognitive profiles were identified:a“typical”group(56.04%of the sample)that demonstrated relatively poorer scores on memory testing than non-memory tests,and an“atypical”group(43.96%of the sample)with smaller differences between memory and non-memory measures,indicating a more uniform pattern of impairment across cognitive domains.While the groups had comparable levels of overall cognitive impairment and cerebrospinal fluid biomarkers of Alzheimer’s disease,the typical group displayed accelerated atrophy rates every 6 months across multiple brain regions(hippocampus:29.02 mm^(3),standard error[SE]=10.13,P=0.005;whole brain:1799.85 mm^(3),SE=781.57,P=0.023;entorhinal cortex:22.26 mm^(3),SE=11.15,P=0.048;fusiform gyrus:66.24 mm^(3),SE=28.53,P=0.021).Survival analysis revealed markedly higher dementia conversion risk(hazard ratio:1.70,95%confidence interval:1.27,2.27,P<0.001)and shorter progression time in the typical group.These findings persisted after controlling for comorbid pathologies.In conclusion,this data-driven approach identified two distinct cognitive subtypes of mild cognitive impairment due to Alzheimer’s disease that differed in their rates of clinical decline and neurodegeneration.These findings could be used to improve prognostic models and inform clinical trial stratification.
基金supported by Fondi Ateneo grants funded by Sapienza University (#RM120172A3160B53) to EBfunds from Jerome-Lejeune Foundation (#1887-2019b) to EBthe European Union–Next Generation EU (Project ECS 0000024Rome Technopole,–CUP B83C22002820006, NRPMission 4 Component 2 Investment 1.5 to LRR)
文摘The increasing prevalence of metabolic disorders and neurodegenerative diseases has uncovered shared pathophysiological pathways,with insulin resistance and mitochondrial dysfunction emerging as critical contributors to cognitive decline.Insulin resistance impairs neuronal metabolism and synaptic function,fostering neurodegeneration as observed in Alzheimer’s disease and Down syndrome.Indeed,Down syndrome,characterized by the triplication of the APP gene,represents a valuable genetic model for studying early-onset Alzheimer’s disease and accelerated aging.Building on the link between metabolic dysfunctions and neurodegeneration,innovative strategies addressed brain insulin resistance as a key driver of cognitive decline.Intranasal insulin has shown promise in improving cognition in early Alzheimer’s disease and type 2 diabetes,supporting the concept that restoring insulin sensitivity can mitigate neurodegeneration.However,insulin-based therapies risk desensitizing insulin signaling,potentially worsening the disease.Incretins,particularly glucagon-like peptide 1 receptor agonists,offer neuroprotective benefits by enhancing insulin sensitivity,metabolism,and synaptic plasticity while reducing oxidative distress and neuroinflammation.This review focuses on current knowledge on the metabolic and molecular interactions between insulin resistance,mitochondrial dynamics(including their roles in energy metabolism),and oxidative distress regulation,as these are pivotal in both Alzheimer’s disease and Down syndrome.By addressing these interconnected mechanisms,innovative treatments may emerge for both metabolic and neurodegenerative disorders.
基金supported by the Elderly Health Research Project of Jiangsu Province,No.LKM2023043(to XZ).
文摘Alterations in RNA methylation may affect the initiation and development of Alzheimer’s disease.However,the exact nature of the relationship between RNA methylation and Alzheimer’s disease remains unclear.In this study,RNA methylation levels were analyzed by bulk transcriptomic and single-cell RNA sequencing.The expression levels of RNA methylation regulators were confirmed using molecular biology techniques.Co-expression network analysis was used to identify relevant long non-coding RNAs.Molecular subtypes related to RNA methylation were classified,and variations in clinical characteristics,biological behavior,and immune signatures between subtypes were assessed.Machine learning approaches were applied to identify methylation-associated long non-coding RNAs,which were used to construct a risk model and nomogram for Alzheimer’s disease.Potential therapeutic agents for different risk groups were predicted,and in vitro experiments were conducted to identify key RNA methylation events.Single-cell analysis demonstrated enhanced RNA methylation in patients with Alzheimer’s disease,particularly within T cells,B cells,and NK cells.Quantitative reverse transcription-polymerase chain reaction and western blot confirmed alterations in RNA methylation regulators in neurons treated with amyloid-βoligomers in vitro.This evidence supported the classification of patients with Alzheimer’s disease into heterogeneous subtypes.Specifically,subtype 1 was identified as the immune-active subtype,while subtype 2 was characterized by a metabolic phenotype.Machine learning algorithms identified five significant methylation-associated long non-coding RNAs-LINC01007,MAP4K3-DT,MIR302CHG,VAC14-AS1,and TGFB2-OT1-that accurately predict clinical outcomes for patients with Alzheimer’s disease.These patients were classified into low-and high-risk categories;the latter group displayed higher immune infiltration,upregulated immune regulatory gene expression,and elevated immune scores and responded better to treatment with arachidonic-trifluoroethane.These findings suggest that dysregulated RNA methylation alters the immune microenvironment in Alzheimer’s disease and is closely associated with its progression.This phenomenon provides novel insights into potential therapeutic strategies for Alzheimer’s disease that target RNA methylation.
基金part of the EU consortium DCog Plast ‘Diet Cognition and Plasticity” funded by the Joint Programming Initiative “A Health Diet for a Healthy Life”(JPI-HDHL) via the BMWFW (BMWFW-10.420/0009-WF/V/3c/2015 and the Medical Research Council UK:MR/N030087/1)(to LA and ST)supported by the PMU-FFF Research Fund (A-16/01/019-AIG)+9 种基金BA by the PMU-Research and Innovation Fund (PMU-RIF)(project 2023-PRE-008-Altendorfer)supported by the Center for Urban Mental Healthby Alzheimer Nederlandthe Zon MW Program Mechanisms Of DEMentia (MODEM)by the Gravitation program iCNS of the Dutch Research Council (NWO)supported by Grant PID2020-114921RB-C21Maria de Maeztu Unit of Excellence grant CEX2021-001234-M funded by MCIU/AEI/and CIBERFESCB16/10/00269, from the Instituto de Salud Carlos III all of them by “ERDF A way of making Europe”the Generalitat de Catalunya’s Agency AGAUR of 2021SGR00687ICREA Award
文摘In Alzheimer’s disease,microglial phagocytosis is engaged in the pathogenesis as it clears abnormal protein accumulations,debris,and apoptotic cells in the early stages of Alzheimer’s disease,but fuels neuroinflammation and accelerates disease progression in later stages.In vivo parabiosis experiments in aged animals have demonstrated that blood-born factors modulate synaptic plasticity,neurogenesis,and microglial responses.We hypothesize that peripheral factors can modulate microglial function and thereby possibly influence Alzheimer’s disease pathology.The objective of this study is to investigate the effects of Alzheimer’s disease serum on microglial phagocytosis.Here,we use an immortalized human microglial cell line in an in vitro parabiosis assay to investigate the impact of the serum from individuals diagnosed with Alzheimer’s disease(n=30)and age-matched controls(n=30)(PRODEM study)on microglial phagocytosis.Exposure to Alzheimer’s disease serum increased microglial phagocytic uptake of pH-sensitive fluorescent particles and downregulated expression of the lysosomal master regulator transcription factor EB(TFEB)and of ATPase H^(+)transporting lysosomal V1 subunit B2(ATP6V1B2),a component of the vacuolar ATPase.To identify serum components that may relate to changes in phagocytosis,serum samples of the Three-City Study(3C Study)were used.In the 3C Study,blood samples were collected up to 12 years before the onset of cognitive decline or dementia and their serum metabolome is well-defined.Microglia exposed to the serum of future Alzheimer’s disease patients from the 3C Study displayed an increased phagocytic uptake compared with the serum of matched controls,depending on the presence of the apolipoprotein Eε4 allele in the Alzheimer’s disease patients.Furthermore,microglial phagocytosis correlated inversely with serum levels of the omega-3 fatty acid eicosapentaenoic acid.We confirmed this inverse correlation between eicosapentaenoic acid and phagocytosis in the serum samples of the PRODEM cohort.In addition,in vitro testing of eicosapentaenoic acid on microglial phagocytosis showed a concentration-dependent decrease in phagocytic uptake.In conclusion,following incubation with Alzheimer’s disease blood serum,we observed increased microglial phagocytic uptake and the downregulation of TFEB and ATP6V1B2,possibly indicating lysosomal dysfunction.Furthermore,microglial phagocytosis was inversely correlated with serum eicosapentaenoic acid levels,suggesting an important role for dietary eicosapentaenoic acid in microglial function.
