Alzheimer's disease protective allele of <i>Clusterin</i> modulates neuronal excitability through lipid-droplet-mediated neuron-glia communication.

ABSTRACT: Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified a plethora of risk loci. However, the disease variants/genes and the underlying mechanisms remain largely unknown. For a strong AD-associated locus near Clusterin (CLU), we tied an AD protective allele to a role of neuronal CLU in promoting neuron excitability through lipid-mediated neuron-glia communication. We identified a putative causal SNP of CLU that impacts neuron-specific chromatin accessibility to transcription-factor(s), with the AD protective allele upregulating neuronal CLU and promoting neuron excitability. Transcriptomic analysis and functional studies in induced pluripotent stem cell (iPSC)-derived neurons co-cultured with mouse astrocytes show that neuronal CLU fac

SUBMITTER: Zhao X 

PROVIDER: S-EPMC11343251 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature