Genetic and multi‐omic risk assessment of Alzheimer's disease implicates core associated biological domains

Alzheimer s & Dementia Translational Research & Clinical Interventions, Journal Year: 2024, Volume and Issue: 10(2)

Published: April 1, 2024

Abstract INTRODUCTION Alzheimer's disease (AD) is the predominant dementia globally, with heterogeneous presentation and penetrance of clinical symptoms, variable presence mixed pathologies, potential subtypes, numerous associated endophenotypes. Beyond difficulty designing treatments that address core pathological characteristics disease, therapeutic development challenged by uncertainty which endophenotypic areas specific targets implicated those endophenotypes to prioritize for further translational research. However, publicly funded consortia driving large‐scale open science efforts have produced multiple omic analyses both risk relevance biological process involvement genes across genome. METHODS Here we report an informatic pipeline draws from genetic association studies, predicted variant impact, linkage phenotypes create a score. This paired multi‐omic score utilizing extensive sets transcriptomic proteomic studies identify system‐level changes in expression AD. These two elements combined constitute our target ranks AD genome‐wide. The ranked are organized into space through 19 domains described genetics genomics accompanying literature. constructed exhaustive Gene Ontology (GO) term compilations, allowing automated assignment objectively defined disease‐associated biology. rank‐and‐organize approach, performed genome‐wide, allows characterization aggregations domains. RESULTS top AD‐risk‐associated Synapse, Immune Response, Lipid Metabolism, Mitochondrial Structural Stabilization, Proteostasis, slightly lower levels enrichment present within other 13 DISCUSSION provides objective methodology localize drill down most significantly GO terms annotated targets.

Language: Английский

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Characterizing molecular and synaptic signatures in mouse models of late‐onset Alzheimer's disease independent of amyloid and tau pathology

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(6), P. 4126 - 4146

Published: May 12, 2024

Abstract INTRODUCTION MODEL‐AD (Model Organism Development and Evaluation for Late‐Onset Alzheimer's Disease) is creating distributing novel mouse models with humanized, clinically relevant genetic risk factors to capture the trajectory progression of late‐onset disease (LOAD) more accurately. METHODS We created LOAD2 model by combining apolipoprotein E4 (APOE4), Trem2*R47H, humanized amyloid‐beta (Aβ). Mice were subjected a control diet or high‐fat/high‐sugar (LOAD2+HFD). assessed disease‐relevant outcome measures in plasma brain including neuroinflammation, Aβ, neurodegeneration, neuroimaging, multi‐omics. RESULTS By 18 months, LOAD2+HFD mice exhibited sex‐specific neuron loss, elevated insoluble Aβ42, increased neurofilament light chain (NfL), altered gene/protein expression related lipid metabolism synaptic function. Imaging showed reductions volume neurovascular uncoupling. Deficits acquiring touchscreen‐based cognitive tasks observed. DISCUSSION The comprehensive characterization reveals that this important preclinical studies seeking understand LOAD prior independent amyloid plaques tau tangles. Highlights unlike (e.g., fed diet, CD), presented subtle but significant loss neurons cortex, levels Ab42 brain, (NfL). Transcriptomics proteomics changes gene/proteins relating variety processes In vivo imaging revealed an age‐dependent reduction region (MRI) uncoupling (PET/CT). also demonstrated deficits acquisition tasks.

Language: Английский

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Extended genome‐wide association study employing the African genome resources panel identifies novel susceptibility loci for Alzheimer's disease in individuals of African ancestry

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(8), P. 5247 - 5261

Published: July 3, 2024

Abstract INTRODUCTION Despite a two‐fold risk, individuals of African ancestry have been underrepresented in Alzheimer's disease (AD) genomics efforts. METHODS Genome‐wide association studies (GWAS) 2,903 AD cases and 6,265 controls ancestry. Within‐dataset results were meta‐analyzed, followed by functional analyses. RESULTS A novel AD‐risk locus was identified MPDZ on chromosome (chr) 9p23 (rs141610415, MAF = 0.002, p 3.68×10 −9 ). Two additional common nine rare loci with suggestive associations ( P < 9×10 −7 Comparison linkage disequilibrium (LD) patterns between datasets higher lower degrees showed differential at chr12q23.2 ASCL1 ), suggesting that this is modulated regional origin local DISCUSSION These analyses AD‐associated suggest degree modulates some associations. Increased sample sets covering as much genetic diversity possible will be critical to identify deconvolute effects. Highlights Genetic significantly impacts risk Disease (AD). Although are twice likely develop AD, they vastly studies. The Genetics Consortium has previously 16 associated American individuals. current expand effort increasing the size extending ancestral including populations from continental Africa. Single variant meta‐analysis genome‐wide significant gene, 11 significance 9×10−7. samples demonstrated differing one these loci, and/or geographic effect locus. findings illustrate importance number fully disentangle architecture underlying yield more effective ancestry‐informed screening tools therapeutic interventions.

Language: Английский

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Microglial MHC-I induction with aging and Alzheimer’s is conserved in mouse models and humans

GeroScience, Journal Year: 2023, Volume and Issue: 45(5), P. 3019 - 3043

Published: July 1, 2023

Language: Английский

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Microglial MHC-I induction with aging and Alzheimer’s is conserved in mouse models and humans

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 10, 2023

Major Histocompatibility Complex I (MHC-I) CNS cellular localization and function is still being determined after previously thought to be absent from the brain. MHC-I expression has been reported increase with brain aging in mouse, rat, human whole tissue analyses but was undetermined. Neuronal proposed regulate developmental synapse elimination tau pathology Alzheimer's disease (AD). Here we report that across newly generated publicly available ribosomal profiling, cell sorting, single-cell data, microglia are primary source of classical non-classical mice humans. Translating Ribosome Affinity Purification-qPCR analysis 3-6 18-22 month old (m.o.) revealed significant age-related microglial induction pathway genes

Language: Английский

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Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(2), P. e0293548 - e0293548

Published: Feb. 15, 2024

RNA sequencing and genetic data support spleen tyrosine kinase (SYK) high affinity immunoglobulin epsilon receptor subunit gamma (FCER1G) as putative targets to be modulated for Alzheimer's disease (AD) therapy. FCER1G is a component of Fc complexes that contain an immunoreceptor tyrosine-based activation motif (ITAM). SYK interacts with the by binding doubly phosphorylated ITAM (p-ITAM) via its two tandem SH2 domains (SYK-tSH2). Interaction p-ITAM SYK-tSH2 enables phosphorylation. Since reported exacerbate AD pathology, we hypothesized disruption this interaction would beneficial patients. Herein, developed biochemical biophysical assays enable discovery small molecules perturb between SYK-tSH2. We identified distinct chemotypes using high-throughput screen (HTS) orthogonally assessed their binding. Both covalently modify inhibit p-ITAM, however, these compounds lack selectivity limits utility chemical tools.

Language: Английский

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New directions for Alzheimer's disease research from the Jackson Laboratory Center for Alzheimer's and Dementia Research 2022 workshop

Alzheimer s & Dementia Translational Research & Clinical Interventions, Journal Year: 2024, Volume and Issue: 10(1)

Published: Jan. 1, 2024

Abstract INTRODUCTION In September 2022, The Jackson Laboratory Center for Alzheimer's and Dementia Research (JAX CADR) hosted a workshop with leading researchers in the disease related dementias (ADRD) field. METHODS During workshop, participants brainstormed new directions to overcome current barriers providing patients effective ADRD therapeutics. outlined specific areas of focus. Following each group used standard literature search methods provide background topic. RESULTS team invited experts identified four key that can be collectively addressed make significant impact field: (1) Prioritize diversification targets, (2) enhance factors promoting resilience, (3) de‐risk clinical pipeline, (4) centralize data management. DISCUSSION this report, we review these objectives propose innovations expedite therapeutic pipelines.

Language: Английский

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Characterizing Molecular and Synaptic Signatures in mouse models of Late-Onset Alzheimer’s Disease Independent of Amyloid and Tau Pathology

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 20, 2023

MODEL-AD is creating and distributing novel mouse models with humanized, clinically relevant genetic risk factors to more accurately mimic LOAD than commonly used transgenic models.

Language: Английский

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Inhibiting mtDNA transcript translation alters Alzheimer's disease‐associated biology

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 23, 2024

Abstract INTRODUCTION Alzheimer's disease (AD) features changes in mitochondrial structure and function. Investigators debate where to position pathology within the chronology context of other AD features. METHODS To address whether dysfunction alters AD‐implicated genes proteins, we treated SH‐SY5Y cells induced pluripotent stem cell (iPSC)‐derived neurons with chloramphenicol, an antibiotic that inhibits mtDNA‐generated transcript translation. We characterized adaptive, AD‐associated gene, protein responses. RESULTS iPSC responded mtDNA translation inhibition by increasing copy number transcription. Nuclear‐expressed respiratory chain mRNA levels also changed. There were AD‐consistent concordant model‐specific amyloid precursor protein, beta amyloid, apolipoprotein E, tau, α‐synuclein biology. DISCUSSION Primary induces compensatory organelle responses, nuclear gene expression, biology proteins ways may recapitulate brain aging molecular phenomena. Highlights In AD, could represent a cause or consequence. inhibited human neuronal neurons. Mitochondrial expression shifted adaptive‐consistent patterns. APP, Aβ, APOE, changed stress creates environment promotes pathology.

Language: Английский

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Open drug discovery in Alzheimer's disease

Alzheimer s & Dementia Translational Research & Clinical Interventions, Journal Year: 2023, Volume and Issue: 9(2)

Published: April 1, 2023

Alzheimer's disease (AD) drug discovery has focused on a set of highly studied therapeutic hypotheses, with limited success. The heterogeneous nature AD processes suggests that more diverse, systems-integrated strategy may identify new hypotheses. Although many target hypotheses have arisen from systems-level modeling human disease, in practice and for reasons, it proven challenging to translate them into pipelines. First, implicate protein targets and/or biological mechanisms are under-studied, meaning there is paucity evidence inform experimental strategies as well high-quality reagents perform them. Second, predicted act concert, requiring adaptations how we characterize targets. Here posit the development open distribution informatic outputs-termed enabling packages (TEPs)-will catalyze rapid evaluation emerging by parallel, independent, unencumbered research.

Language: Английский

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