Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer’s disease risk gene SORL1
Hyo Lee,
Aimee J. Aylward,
Richard V. Pearse, II,
Alexandra M. Lish,
Yi-Chen Hsieh,
Zachary M. Augur,
Courtney R. Benoit,
Vicky Chou,
Allison Knupp,
Cheryl Pan,
Srilakshmi Goberdhan,
Duc M. Duong,
Nicholas T. Seyfried,
David A. Bennett,
Mariko F. Taga,
Kevin Huynh,
Matthias Arnold,
Peter J. Meikle,
Philip L. De Jager,
Vilas Menon,
Jessica E. Young,
Tracy L. Young-Pearse
Affiliations
Hyo Lee
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Aimee J. Aylward
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Richard V. Pearse, II
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Alexandra M. Lish
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Yi-Chen Hsieh
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Zachary M. Augur
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Courtney R. Benoit
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Vicky Chou
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Allison Knupp
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
Cheryl Pan
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Srilakshmi Goberdhan
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Duc M. Duong
Department of Biochemistry, Emory School of Medicine, Atlanta, GA, USA
Nicholas T. Seyfried
Department of Biochemistry, Emory School of Medicine, Atlanta, GA, USA
David A. Bennett
Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
Mariko F. Taga
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
Kevin Huynh
Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Bundoora, VIC, Australia
Matthias Arnold
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
Peter J. Meikle
Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Bundoora, VIC, Australia
Philip L. De Jager
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
Vilas Menon
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
Jessica E. Young
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
Tracy L. Young-Pearse
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; Corresponding author
Summary: 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 β (TGF-β)/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.
