Towards cascading genetic risk in Alzheimer’s disease

Brain, Journal Year: 2024, Volume and Issue: 147(8), P. 2680 - 2690

Published: May 30, 2024

Abstract Alzheimer’s disease typically progresses in stages, which have been defined by the presence of disease-specific biomarkers: amyloid (A), tau (T) and neurodegeneration (N). This progression biomarkers has condensed into ATN framework, each can be either positive (+) or negative (−). Over past decades, genome-wide association studies implicated ∼90 different loci involved with development late-onset disease. Here, we investigate whether genetic risk for contributes equally to stages it exhibits a stage-dependent effect. Amyloid (A) status was using combination available PET CSF Disease Neuroimaging Initiative cohort. In 312 participants biomarker-confirmed A−T− status, used Cox proportional hazards models estimate contribution APOE polygenic scores (beyond APOE) convert A+T− (65 conversions). Furthermore, repeated analysis 290 investigated conversion A+T+ (45 Both survival analyses were adjusted age, sex years education. For from A+T−, APOE-e4 burden showed significant effect [hazard ratio (HR) = 2.88; 95% confidence interval (CI): 1.70–4.89; P < 0.001], whereas did not (HR 1.09; CI: 0.84–1.42; 0.53). Conversely, transition A+T+, reduced 1.62; 1.05–2.51; 0.031), an increased 1.73; 1.27–2.36; 0.001). The marginal driven e4 homozygotes 2.58; 1.05–6.35; 0.039) as opposed heterozygotes 1.74; 0.87–3.49; 0.12). unfolds fashion. A better understanding interplay between stage lead more mechanistic molecular processes leading disease, addition opening therapeutic windows targeted interventions.

Language: Английский

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Neuronal A2A receptor exacerbates synapse loss and memory deficits in APP/PS1 mice

Brain, Journal Year: 2024, Volume and Issue: 147(8), P. 2691 - 2705

Published: July 5, 2024

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

Language: Английский

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Integrative single-nucleus multi-omics analysis prioritizes candidate cis and trans regulatory networks and their target genes in Alzheimer’s disease brains

Cell & Bioscience, Journal Year: 2023, Volume and Issue: 13(1)

Published: Oct. 3, 2023

The genetic underpinnings of late-onset Alzheimer's disease (LOAD) are yet to be fully elucidated. Although numerous LOAD-associated loci have been discovered, the causal variants and their target genes remain largely unknown. Since brain is composed heterogenous cell subtypes, it imperative study on a subtype specific level explore biological processes underlying LOAD. Here, we present largest parallel single-nucleus (sn) multi-omics simultaneously profile gene expression (snRNA-seq) chromatin accessibility (snATAC-seq) date, using nuclei from 12 normal LOAD brains. We identified clusters based profiles characterized subtype-specific differentially expressed (DEGs), accessible peaks (DAPs) cis co-accessibility networks (CCANs). Integrative analysis defined disease-relevant CCANs in multiple subtypes discovered candidate regulatory elements (cCREs), genes, trans-interacting transcription factors (TFs), some which, including ELK1, JUN, SMAD4 excitatory neurons, were also LOAD-DEGs. Finally, focused subset that overlap known LOAD-GWAS regions catalogued putative functional SNPs changing affinities TF motifs within LOAD-cCREs linked LOAD-DEGs, APOE MYO1E microglia BIN1 subpopulation oligodendrocytes. To our knowledge, this represents most comprehensive systematic interrogation date impact dysregulation at resolution. Our findings reveal crosstalk between epigenetic, genomic, transcriptomic determinants pathogenesis define catalogues cCREs, involved etiology which they act exert pathogenic effects. Overall, these results suggest cis-trans interactions TFs, dysregulated by contribute development

Language: Английский

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Lessons from genetic studies in Alzheimer disease

Revue Neurologique, Journal Year: 2024, Volume and Issue: 180(5), P. 368 - 377

Published: Feb. 29, 2024

Language: Английский

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Obesity affects brain cortex gene expression in an APOE genotype and sex dependent manner

International Journal of Obesity, Journal Year: 2024, Volume and Issue: 48(6), P. 841 - 848

Published: March 7, 2024

Language: Английский

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