PICALM Alzheimer’s Risk Allele Causes Aberrant Lipid Droplets in Microglia

Authors

Alena Kozlova
Siwei Zhang
Ari Sudwarts
Hanwen Zhang
Stanislau Smirnou
Seul Kee Byeon
Christina Thapa
Xiaotong Sun
Kimberley Stephenson
Xiaojie Zhao
Brendan Jamison
Moorthi Ponnusamy
Xin He
Julie A Schneider
Akhilesh Pandey
David A Bennett
Zhiping P Pang
Alan R Sanders
Hugo J Bellen
Gopal Thinakaran
Jubao Duan

Language

English

Publication Date

10-1-2025

Journal

Nature

DOI

10.1038/s41586-025-09486-x

PMID

40903578

PMCID

PMC12571902

PubMedCentral® Posted Date

9-3-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Despite genome-wide association studies (GWAS) of late-onset Alzheimer’s disease (LOAD) having identified many genetic risk loci1–3, the underlying disease mechanisms remain largely unclear. Determining causal disease variants and their LOAD-relevant cellular phenotypes has been a challenge. Here, using our approach for identifying functional GWAS risk variants showing allele-specific open chromatin, we systematically identified putative causal LOAD-risk variants in human induced pluripotent stem (iPS)-cell-derived neurons, astrocytes and microglia, and linked a PICALM LOAD-risk allele to a microglial-specific role of PICALM in lipid droplet (LD) accumulation. Allele-specific open-chromatin mapping revealed functional risk variants for 26 LOAD-risk loci, mostly specific to microglia. At the microglial-specific PICALM locus, the LOAD-risk allele of the single-nucleotide polymorphism rs10792832 reduced transcription factor (PU.1) binding and PICALM expression, impairing the uptake of amyloid beta (Aβ) and myelin debris. Notably, microglia carrying the PICALM risk allele showed transcriptional enrichment of pathways for cholesterol synthesis and LD formation. Genetic and pharmacological perturbations of microglia further established a causal link between reduced PICALM expression, LD accumulation and phagocytosis deficits. Our work elucidates the selective LOAD vulnerability in microglia at the PICALM locus through detrimental LD accumulation, providing a neurobiological basis that can be exploited for developing clinical interventions.

Keywords

Animals, Humans, Alleles, Alzheimer Disease, Amyloid beta-Peptides, Astrocytes, Cholesterol, Chromatin, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Induced Pluripotent Stem Cells, Lipid Droplets, Microglia, Myelin Sheath, Neurons, Phagocytosis, Polymorphism, Single Nucleotide, Monomeric Clathrin Assembly Proteins, Genetics of the nervous system

Published Open-Access

yes

Recommended Citation

Kozlova, Alena; Zhang, Siwei; Sudwarts, Ari; et al., "PICALM Alzheimer’s Risk Allele Causes Aberrant Lipid Droplets in Microglia" (2025). Faculty and Staff Publications. 2131.
https://digitalcommons.library.tmc.edu/baylor_docs/2131