Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer’s disease pathology

Cell, Год журнала: 2023, Номер 186(20), С. 4365 - 4385.e27

Опубликована: Сен. 1, 2023

Alzheimer's disease (AD) is the most common cause of dementia worldwide, but molecular and cellular mechanisms underlying cognitive impairment remain poorly understood. To address this, we generated a single-cell transcriptomic atlas aged human prefrontal cortex covering 2.3 million cells from postmortem brain samples 427 individuals with varying degrees AD pathology impairment. Our analyses identified AD-pathology-associated alterations shared between excitatory neuron subtypes, revealed coordinated increase cohesin complex DNA damage response factors in neurons oligodendrocytes, uncovered genes pathways associated high function, dementia, resilience to pathology. Furthermore, selectively vulnerable somatostatin inhibitory subtypes depleted AD, discovered two distinct groups that were more abundant preserved function late life, link

Язык: Английский

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Single-cell multiregion dissection of Alzheimer’s disease

Nature, Год журнала: 2024, Номер 632(8026), С. 858 - 868

Опубликована: Июль 24, 2024

Abstract Alzheimer’s disease is the leading cause of dementia worldwide, but cellular pathways that underlie its pathological progression across brain regions remain poorly understood 1–3 . Here we report a single-cell transcriptomic atlas six different in aged human brain, covering 1.3 million cells from 283 post-mortem samples 48 individuals with and without disease. We identify 76 cell types, including region-specific subtypes astrocytes excitatory neurons an inhibitory interneuron population unique to thalamus distinct canonical subclasses. vulnerable populations are depleted specific disease, provide evidence Reelin signalling pathway involved modulating vulnerability these neurons. develop scalable method for discovering gene modules, which use cell-type-specific modules altered annotate differences associated diverse variables. astrocyte program cognitive resilience pathology, tying choline metabolism polyamine biosynthesis preserved function late life. Together, our study develops regional ageing provides insights into vulnerability, response pathology.

Язык: Английский

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Updates on mouse models of Alzheimer’s disease

Molecular Neurodegeneration, Год журнала: 2024, Номер 19(1)

Опубликована: Март 11, 2024

Abstract Alzheimer’s disease (AD) is the most common neurodegenerative in United States (US). Animal models, specifically mouse models have been developed to better elucidate mechanisms and test therapeutic strategies for AD. A large portion of effort field was focused on developing transgenic (Tg) through over-expression genetic mutations associated with familial AD (FAD) patients. Newer generations knock-in (KI)/knock-out (KO) or CRISPR gene editing technologies, both sporadic risk genes hope more accurately model proteinopathies without human brains. In this review, we summarized phenotypes a few commonly used as well newly translational research laboratories including presence absence key pathological features such amyloid tau pathology, synaptic neuronal degeneration cognitive behavior deficits. addition, advantages limitations these elaborated along discussions any sex-specific features. More importantly, omics data from available analyzed categorize molecular signatures each reminiscent brain changes, guide future selection suitable specific questions be addressed field.

Язык: Английский

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Xenografted human microglia display diverse transcriptomic states in response to Alzheimer’s disease-related amyloid-β pathology

Nature Neuroscience, Год журнала: 2024, Номер 27(5), С. 886 - 900

Опубликована: Март 27, 2024

Abstract Microglia are central players in Alzheimer’s disease pathology but analyzing microglial states human brain samples is challenging due to genetic diversity, postmortem delay and admixture of pathologies. To circumvent these issues, here we generated 138,577 single-cell expression profiles stem cell-derived microglia xenotransplanted the App NL-G-F model amyloid wild-type controls. Xenografted adopt a disease-associated profile similar that seen mouse microglia, display more pronounced leukocyte antigen or HLA state, likely related presentation response plaques. The also involves pro-inflammatory cytokine/chemokine cytokine CRM oligomeric Aβ oligomers. Genetic deletion TREM2 APOE as well polymorphisms R47H transplanted modulate responses differentially. other risk genes differentially regulated across distinct cell elicited pathology. Thus, have identified multiple transcriptomic adopted by multipronged disease-related pathology, which should be taken into account translational studies.

Язык: Английский

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Cellular and pathological functions of tau

Nature Reviews Molecular Cell Biology, Год журнала: 2024, Номер 25(11), С. 845 - 864

Опубликована: Июль 16, 2024

Язык: Английский

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Biomimetic Nanovesicles as a Dual Gene Delivery System for the Synergistic Gene Therapy of Alzheimer’s Disease

ACS Nano, Год журнала: 2024, Номер 18(18), С. 11753 - 11768

Опубликована: Апрель 22, 2024

The association between dysfunctional microglia and amyloid-β (Aβ) is a fundamental pathological event increases the speed of Alzheimer's disease (AD). Additionally, pathogenesis AD intricate single drug may not be enough to achieve satisfactory therapeutic outcome. Herein, we reported facile effective gene therapy strategy for modulation function intervention Aβ anabolism by ROS-responsive biomimetic exosome-liposome hybrid nanovesicles (designated as TSEL). codelivery β-site amyloid precursor protein cleaving enzyme-1 (BACE1) siRNA (siBACE1) TREM2 plasmid (pTREM2) efficiently penetrate blood-brain barrier enhance accumulation at lesions with help exosomes homing ability angiopep-2 peptides. Specifically, an upregulation expression can reprogram from pro-inflammatory M1 phenotype anti-inflammatory M2 while also restoring its capacity phagocytose nerve repair function. In addition, reduces production plaques source knocking out BACE1 gene, which expected further effect AD. in vivo study suggests that TSEL through synergistic two drugs ameliorate APP/PS1 mice cognitive impairment regulating activated microglial phenotype, reducing Aβ, preventing retriggering neuroinflammation. This employs delivery dual nucleic acids, achieving AD, thus offering more options treatment

Язык: Английский

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Inflammatory aspects of Alzheimer’s disease

Acta Neuropathologica, Год журнала: 2024, Номер 148(1)

Опубликована: Авг. 28, 2024

Язык: Английский

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sc2GWAS: a comprehensive platform linking single cell and GWAS traits of human

Nucleic Acids Research, Год журнала: 2024, Номер 53(D1), С. D1151 - D1161

Опубликована: Ноя. 20, 2024

Abstract Identifying cell populations associated with risk variants is essential for uncovering cell-specific mechanisms that drive disease development and progression. Integrating genome-wide association studies (GWAS) single-cell RNA sequencing (scRNA-seq) has become an effective strategy detecting trait–cell relationships. The accumulation of trait-related single data led to urgent need its comprehensively processing. To address this, we developed sc2GWAS (https://bio.liclab.net/sc2GWAS/), which aims document large-scale GWAS regulatory pairs at resolution provide comprehensive annotations enrichment analyses these related pairs. current version curates a total 15 078 310 candidate from > 6 300 000 individual cells, offering valuable resource exploring complex relationships between traits cells. We applied strict quality control measures on both scRNA-seq data, ensuring the reliability accuracy datasets identification trait-relevant cells genes. In addition, provides ranked lists genes extensive (epi) genetic annotations, making it downstream analyses. demonstrate utility platform by investigating Alzheimer’s disease, where identified significant associations microglial APOE gene emerging as particularly significant. This facilitates detailed research into trait–gene interactions, anticipate will mechanisms.

Язык: Английский

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A single-cell and spatial RNA-seq database for Alzheimer’s disease (ssREAD)

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июнь 6, 2024

Abstract Alzheimer’s Disease (AD) pathology has been increasingly explored through single-cell and single-nucleus RNA-sequencing (scRNA-seq & snRNA-seq) spatial transcriptomics (ST). However, the surge in data demands a comprehensive, user-friendly repository. Addressing this, we introduce RNA-seq database for disease (ssREAD). It offers broader spectrum of AD-related datasets, an optimized analytical pipeline, improved usability. The encompasses 1,053 samples (277 integrated datasets) from 67 scRNA-seq snRNA-seq studies, totaling 7,332,202 cells. Additionally, it archives 381 ST datasets 18 human mouse brain studies. Each dataset is annotated with details such as species, gender, region, disease/control status, age, AD Braak stages. ssREAD also provides analysis suite cell clustering, identification differentially expressed spatially variable genes, cell-type-specific marker genes regulons, spot deconvolution integrative analysis. freely available at https://bmblx.bmi.osumc.edu/ssread/ .

Язык: Английский

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Tracking neuroinflammatory biomarkers in Alzheimer’s disease: a strategy for individualized therapeutic approaches?

Journal of Neuroinflammation, Год журнала: 2024, Номер 21(1)

Опубликована: Июль 30, 2024

Abstract Background Recent trials of anti-amyloid-β (Aβ) monoclonal antibodies, including lecanemab and donanemab, in early Alzheimer disease (AD) showed that these drugs have limited clinical benefits their use comes with a significant risk serious adverse events. Thus, it seems crucial to explore complementary therapeutic approaches. Genome-wide association studies identified robust associations between AD several genes related immune response, but not restricted CD33 TREM2 . Here, we critically reviewed the current knowledge on candidate neuroinflammatory biomarkers role characterizing pathophysiology AD. Main body Neuroinflammation is recognized be contributing component pathogenesis. The fact neuroinflammation most likely present from earliest pre-stages co-occurs deposition Aβ reinforces need precisely define sequence nature Numerous involving anti-inflammatory previously yielded unfavorable outcomes mild-to-moderate Although reasons behind failures remain unclear, may include time target selected for intervention. Indeed, our review, observed stage-dependent process brain. While initial activation glial cells counteracts brain deposition, downregulation functional state microglia occurs at more advanced stages. To address this issue, personalized modulation therapy required. emergence reliable blood-based biomarkers, particularly fibrillary acidic protein, marker reactive astrocytes, facilitate classification patients based ATI(N) biomarker framework. This expands upon traditional (“A”), tau (“T”), neurodegeneration (“N”), by incorporating novel inflammatory (“I”). Conclusions review outlines potential and, importantly, emphasizes longitudinal analyses, which are needed accurately monitor dynamics cerebral inflammation. Such precise information place will required before interventions can considered evaluation. We propose an effective anti-neuroinflammatory should specifically while considering individual status patients.

Язык: Английский

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