Year: 2024
Type: article
Abstract: . However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease.
Source: Nature
Authors: Michael S. Haney, Róbert Pálovics, Christy Nicole Munson, Chris Long, Patrik K. Johansson, Oscar Yip, Wentao Dong, Eshaan Rawat, Elizabeth West, Johannes C. M. Schlachetzki, Andy Tsai, Ian Hunter Guldner, Bhawika S. Lamichhane, Amanda Smith, Nicholas Schaum, Kruti Calcuttawala, Andrew Shin, Yung-Hua Wang, Chengzhong Wang, Nicole Koutsodendris, Geidy E. Serrano, Thomas G. Beach, Eric M. Reiman, Christopher K. Glass, Monther Abu-Remaileh, Annika Enejder, Yadong Huang, Tony Wyss-Coray
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,290
Awards: G1606131442, G2161113364, G3250808129, G3251040009, G3521153818, Microglial lipid droplets in Alzheimer's disease, G6030318873, Arizona Alzheimer's Disease Core Center, National Brain and Tissue Resource for Parkinson's Disease and Related Disorders, G7836467104, Imaging the metabolic and phagocytic landscape of microglia in Alzheimer’s disease, UCSD Shiley-Marcos Alzheimer's Disease Research Center P30, Stanford Medicine Center for Longevity and Healthy Aging, Arizona Alzheimer's Disease Research Center, Stanford Alzheimer's Disease Research Center, APOE in the Predisposition to, Protection from and Prevention of Alzheimer's Disease, Decoding the Multifactorial Etiology of Neural Network Dysfunction in Alzheimer's Disease, Training in Basic Research on Aging and Age-Related Disease, G961669115
OpenAlex ID: W4392762752