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APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia.

Authors :: Haney MS
Pálovics R
Munson CN
Long C
Johansson PK
Yip O
Dong W
Rawat E
West E
Schlachetzki JCM
Tsai A
Guldner IH
Lamichhane BS
Smith A
Schaum N
Calcuttawala K
Shin A
Wang YH
Wang C
Koutsodendris N
Serrano GE
Beach TG
Reiman EM
Glass CK
Abu-Remaileh M
Enejder A
Huang Y
Wyss-Coray T
Source :: Nature [Nature] 2024 Apr; Vol. 628 (8006), pp. 154-161. Date of Electronic Publication: 2024 Mar 13.
Publication Year :: 2024
Abstract: Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells <superscript>1</superscript> . 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.<br /> (© 2024. The Author(s).)