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Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer's disease risk gene SORL1.
Lee, Hyo; Aylward, Aimee J; Pearse, Richard V; Lish, Alexandra M; Hsieh, Yi-Chen; Augur, Zachary M; Benoit, Courtney R; Chou, Vicky; Knupp, Allison; Pan, Cheryl; Goberdhan, Srilakshmi; Duong, Duc M; Seyfried, Nicholas T; Bennett, David A; Taga, Mariko F; Huynh, Kevin; Arnold, Matthias; Meikle, Peter J; De Jager, Philip L; Menon, Vilas; Young, Jessica E; Young-Pearse, Tracy L.
Afiliação
  • Lee H; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Aylward AJ; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Pearse RV; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Lish AM; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Hsieh YC; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Augur ZM; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Benoit CR; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Chou V; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Knupp A; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
  • Pan C; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Goberdhan S; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Duong DM; Department of Biochemistry, Emory School of Medicine, Atlanta, GA, USA.
  • Seyfried NT; Department of Biochemistry, Emory School of Medicine, Atlanta, GA, USA.
  • Bennett DA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
  • Taga MF; Center for Translational and Computational Neuroimmunology, Department of Neurology and the Taub Institute for the Study of Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA.
  • Huynh K; Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Bundoora, VIC, Australia.
  • Arnold M; Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA.
  • Meikle PJ; Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Bundoora, VIC, Australia.
  • De Jager PL; Center for Translational and Computational Neuroimmunology, Department of Neurology and the Taub Institute for the Study of Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA.
  • Menon V; Center for Translational and Computational Neuroimmunology, Department of Neurology and the Taub Institute for the Study of Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA.
  • Young JE; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
  • Young-Pearse TL; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: tpearse@bwh.harvard.edu.
Cell Rep ; 42(8): 112994, 2023 08 29.
Article em En | MEDLINE | ID: mdl-37611586
SORL1 is implicated in the pathogenesis of Alzheimer's disease (AD) through genetic studies. To interrogate the roles of SORL1 in human brain cells, SORL1-null induced pluripotent stem cells (iPSCs) were differentiated to neuron, astrocyte, microglial, and endothelial cell fates. Loss of SORL1 leads to alterations in both overlapping and distinct pathways across cell types, with the greatest effects in neurons and astrocytes. SORL1 loss induces a neuron-specific reduction in apolipoprotein E (APOE) and clusterin (CLU) and altered lipid profiles. Analyses of iPSCs derived from a large cohort reveal a neuron-specific association between SORL1, APOE, and CLU levels, a finding validated in postmortem brain. Enhancement of retromer-mediated trafficking rescues tau phenotypes observed in SORL1-null neurons but does not rescue APOE levels. Pathway analyses implicate transforming growth factor ß (TGF-ß)/SMAD signaling in SORL1 function, and modulating SMAD signaling in neurons alters APOE RNA levels in a SORL1-dependent manner. Taken together, these data provide a mechanistic link between strong genetic risk factors for AD.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Clusterina / Doença de Alzheimer Tipo de estudo: Etiology_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Cell Rep Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Clusterina / Doença de Alzheimer Tipo de estudo: Etiology_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Cell Rep Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos