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APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia.
Haney, Michael S; Pálovics, Róbert; Munson, Christy Nicole; Long, Chris; Johansson, Patrik K; Yip, Oscar; Dong, Wentao; Rawat, Eshaan; West, Elizabeth; Schlachetzki, Johannes C M; Tsai, Andy; Guldner, Ian Hunter; Lamichhane, Bhawika S; Smith, Amanda; Schaum, Nicholas; Calcuttawala, Kruti; Shin, Andrew; Wang, Yung-Hua; Wang, Chengzhong; Koutsodendris, Nicole; Serrano, Geidy E; Beach, Thomas G; Reiman, Eric M; Glass, Christopher K; Abu-Remaileh, Monther; Enejder, Annika; Huang, Yadong; Wyss-Coray, Tony.
Afiliação
  • Haney MS; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Pálovics R; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
  • Munson CN; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Long C; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
  • Johansson PK; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Yip O; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
  • Dong W; Department of Materials Science & Engineering Department, Stanford University School of Medicine, Stanford, CA, USA.
  • Rawat E; Department of Materials Science & Engineering Department, Stanford University School of Medicine, Stanford, CA, USA.
  • West E; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
  • Schlachetzki JCM; The Institute for Chemistry, Engineering & Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA, USA.
  • Tsai A; The Institute for Chemistry, Engineering & Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA, USA.
  • Guldner IH; Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, CA, USA.
  • Lamichhane BS; Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, CA, USA.
  • Smith A; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Schaum N; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
  • Calcuttawala K; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Shin A; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
  • Wang YH; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Wang C; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
  • Koutsodendris N; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Serrano GE; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
  • Beach TG; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Reiman EM; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
  • Glass CK; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Abu-Remaileh M; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
  • Enejder A; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Huang Y; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
  • Wyss-Coray T; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
Nature ; 628(8006): 154-161, 2024 Apr.
Article em En | MEDLINE | ID: mdl-38480892
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 cells1. 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 Aß 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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Microglia / Apolipoproteína E4 / Doença de Alzheimer / Gotículas Lipídicas Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Microglia / Apolipoproteína E4 / Doença de Alzheimer / Gotículas Lipídicas Idioma: En Ano de publicação: 2024 Tipo de documento: Article