Alzheimer's disease risk allele of PICALM causes detrimental lipid droplets in microglia.

Autor:	Kozlova A; Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA., Zhang S; Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA.; Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL 60637, USA., Sudwarts A; Byrd Alzheimer's Center and Research Institute, University of South Florida, Tampa, FL 33613, USA.; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA., Zhang H; Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA., Smirnou S; Byrd Alzheimer's Center and Research Institute, University of South Florida, Tampa, FL 33613, USA.; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA., Sun X; Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA., Stephenson K; Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA., Zhao X; Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA., Jamison B; Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA., Ponnusamy M; Byrd Alzheimer's Center and Research Institute, University of South Florida, Tampa, FL 33613, USA.; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA., He X; Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA.; Department of Neuroscience and Cell Biology, Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA., Pang ZP; Grossman Institute for Neuroscience, Quantitative Biology and Human Behavior, The University of Chicago, Chicago, IL 60637, USA., Sanders AR; Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA.; Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL 60637, USA., Bellen HJ; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA., Thinakaran G; Byrd Alzheimer's Center and Research Institute, University of South Florida, Tampa, FL 33613, USA.; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA., Duan J; Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA.; Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL 60637, USA.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2024 May 24. Date of Electronic Publication: 2024 May 24.
DOI:	10.21203/rs.3.rs-4407146/v1
Abstrakt:	Despite genome-wide association studies of late-onset Alzheimer's disease (LOAD) having identified many genetic risk loci 1-6 , the underlying disease mechanisms remain largely unknown. Determining causal disease variants and their LOAD-relevant cellular phenotypes has been a challenge. Leveraging our approach for identifying functional GWAS risk variants showing allele-specific open chromatin (ASoC) 7 , we systematically identified putative causal LOAD risk variants in human induced pluripotent stem cells (iPSC)-derived neurons, astrocytes, and microglia (MG) and linked PICALM risk allele to a previously unappreciated MG-specific role of PICALM in lipid droplet (LD) accumulation. ASoC mapping uncovered functional risk variants for 26 LOAD risk loci, mostly MG-specific. At the MG-specific PICALM locus, the LOAD risk allele of rs10792832 reduced transcription factor (PU.1) binding and PICALM expression, impairing the uptake of amyloid beta (Aβ) and myelin debris. Interestingly, MG with PICALM risk allele showed transcriptional enrichment of pathways for cholesterol synthesis and LD formation. Genetic and pharmacological perturbations of MG further established a causal link between the reduced PICALM expression, LD accumulation, and phagocytosis deficits. Our work elucidates the selective LOAD vulnerability in microglia for the PICALM locus through detrimental LD accumulation, providing a neurobiological basis that can be exploited for developing novel clinical interventions. Competing Interests: Competing interests The authors declared no competing interests.
Databáze:	MEDLINE
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