Dataset Information

Endo-lysosomal dysregulations and late-onset Alzheimer's disease: impact of genetic risk factors.

ABSTRACT: Increasing evidence supports that cellular dysregulations in the degradative routes contribute to the initiation and progression of neurodegenerative diseases, including Alzheimer's disease. Autophagy and endolysosomal homeostasis need to be maintained throughout life as they are major cellular mechanisms involved in both the production of toxic amyloid peptides and the clearance of misfolded or aggregated proteins. As such, alterations in endolysosomal and autophagic flux, as a measure of degradation activity in these routes or compartments, may directly impact as well on disease-related mechanisms such as amyloid-? clearance through the blood-brain-barrier and the interneuronal spreading of amyloid-? and/or Tau seeds, affecting synaptic function, plasticity and metabolism. The emerging of several genetic risk factors for late-onset Alzheimer's disease that are functionally related to endocytic transport regulation, including cholesterol metabolism and clearance, supports the notion that in particular the autophagy/lysosomal flux might become more vulnerable during ageing thereby contributing to disease onset. In this review we discuss our current knowledge of the risk genes APOE4, BIN1, CD2AP, PICALM, PLD3 and TREM2 and their impact on endolysosomal (dys)regulations in the light of late-onset Alzheimer's disease pathology.

SUBMITTER: Van Acker ZP

PROVIDER: S-EPMC6547588 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Endo-lysosomal dysregulations and late-onset Alzheimer's disease: impact of genetic risk factors.

Van Acker Zoë P ZP Bretou Marine M Annaert Wim W

Molecular neurodegeneration 20190603 1

Increasing evidence supports that cellular dysregulations in the degradative routes contribute to the initiation and progression of neurodegenerative diseases, including Alzheimer's disease. Autophagy and endolysosomal homeostasis need to be maintained throughout life as they are major cellular mechanisms involved in both the production of toxic amyloid peptides and the clearance of misfolded or aggregated proteins. As such, alterations in endolysosomal and autophagic flux, as a measure of degra ...[more]

PMID: 31159836

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Project description:BACKGROUND:New genetic and genomic resources have identified multiple genetic risk factors for late-onset Alzheimer's disease (LOAD) and characterized this common dementia at the molecular level. Experimental studies in model organisms can validate these associations and elucidate the links between specific genetic factors and transcriptomic signatures. Animal models based on LOAD-associated genes can potentially connect common genetic variation with LOAD transcriptomes, thereby providing novel insights into basic biological mechanisms underlying the disease. METHODS:We performed RNA-Seq on whole brain samples from a panel of six-month-old female mice, each carrying one of the following mutations: homozygous deletions of Apoe and Clu; hemizygous deletions of Bin1 and Cd2ap; and a transgenic APOE?4. Similar data from a transgenic APP/PS1 model was included for comparison to early-onset variant effects. Weighted gene co-expression network analysis (WGCNA) was used to identify modules of correlated genes and each module was tested for differential expression by strain. We then compared mouse modules with human postmortem brain modules from the Accelerating Medicine's Partnership for AD (AMP-AD) to determine the LOAD-related processes affected by each genetic risk factor. RESULTS:Mouse modules were significantly enriched in multiple AD-related processes, including immune response, inflammation, lipid processing, endocytosis, and synaptic cell function. WGCNA modules were significantly associated with Apoe-/-, APOE?4, Clu-/-, and APP/PS1 mouse models. Apoe-/-, GFAP-driven APOE?4, and APP/PS1 driven modules overlapped with AMP-AD inflammation and microglial modules; Clu-/- driven modules overlapped with synaptic modules; and APP/PS1 modules separately overlapped with lipid-processing and metabolism modules. CONCLUSIONS:This study of genetic mouse models provides a basis to dissect the role of AD risk genes in relevant AD pathologies. We determined that different genetic perturbations affect different molecular mechanisms comprising AD, and mapped specific effects to each risk gene. Our approach provides a platform for further exploration into the causes and progression of AD by assessing animal models at different ages and/or with different combinations of LOAD risk variants.

Dataset Information

Endo-lysosomal dysregulations and late-onset Alzheimer's disease: impact of genetic risk factors.

Publications

Endo-lysosomal dysregulations and late-onset Alzheimer's disease: impact of genetic risk factors.

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