
==== Front
Res Sq
ResearchSquare
Research Square
American Journal Experts

10.21203/rs.3.rs-4407146/v1
10.21203/rs.3.rs-4407146
preprint
1
Article
Alzheimer’s disease risk allele of PICALM causes detrimental lipid droplets in microglia
Duan Jubao https://orcid.org/0000-0002-7215-3220

Kozlova Alena
Zhang Siwei
Sudwards Ari
Zhang Hanwen https://orcid.org/0000-0001-8490-918X

Smirnou Stanislau
Sun Xiaotong
Stephenson Kimberly
Zhao Xiaojie
Jamison Brendan
Ponnusamy Moorthi
He Xin https://orcid.org/0000-0001-9011-5212

Pang Zhiping https://orcid.org/0000-0002-6183-1233

Sanders Alan https://orcid.org/0000-0001-6629-4011

Bellen Hugo https://orcid.org/0000-0001-5992-5989

Thinakaran Gopal https://orcid.org/0000-0001-5523-6780

24 5 2024
rs.3.rs-4407146https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
https://www.researchsquare.com/article/rs-4407146/v1
nihpp-rs4407146v1.pdf
Abstract

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.
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