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

Cell Reports (Aug 2023)

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

Journal volume & issue: Vol. 42, no. 8
p. 112994

Abstract

Read online

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.

CP: Neuroscience

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

About the journal

Abstract

Keywords