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APOE4/4 is linked to damaging lipid droplets in Alzheimer's microglia.
Haney, Michael S; Pálovics, Róbert; Munson, Christy Nicole; Long, Chris; Johansson, Patrik; Yip, Oscar; Dong, Wentao; Rawat, Eshaan; West, Elizabeth; Schlachetzki, Johannes Cm; 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 94305, USA.
  • Pálovics R; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
  • Munson CN; Equal contribution.
  • Long C; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Johansson P; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
  • Yip O; Equal contribution.
  • Dong W; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Rawat E; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
  • West E; Department of Materials Science & Engineering Department, Stanford University, Stanford, CA 94305, USA.
  • Schlachetzki JC; Department of Materials Science & Engineering Department, Stanford University, Stanford, CA 94305, USA.
  • Tsai A; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, US.
  • Guldner IH; The Institute for Chemistry, Engineering & Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA, USA.
  • Lamichhane BS; The Institute for Chemistry, Engineering & Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA, USA.
  • Smith A; Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, CA 92093, USA.
  • Schaum N; Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, CA 92093, USA.
  • Calcuttawala K; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, 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 94305, 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 94305, 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 94305, 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 94305, 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 94305, USA.
  • Huang Y; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
  • Wyss-Coray T; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
bioRxiv ; 2023 Jul 25.
Article em En | MEDLINE | ID: mdl-37546938
Several genetic risk factors for Alzheimer's Disease (AD) implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells. However, the relationship between lipid metabolism in glia and AD pathology remains poorly understood. Through single-nucleus RNA-sequencing of AD brain tissue, we have identified a microglial state defined by the expression of the lipid droplet (LD) associated enzyme ACSL1 with ACSL1-positive microglia most abundant in AD patients with the APOE4/4 genotype. In human iPSC-derived microglia (iMG) fibrillar Aß (fAß) induces ACSL1 expression, triglyceride synthesis, and LD accumulation in an APOE-dependent manner. Additionally, conditioned media from LD-containing microglia leads to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for AD with microglial LD accumulation and neurotoxic microglial-derived factors, potentially providing novel therapeutic strategies for AD.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
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PubMed Links
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article