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 2nd; 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

doi:10.1016/j.celrep.2023.112994

Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer's disease risk gene SORL1

Cell Rep. 2023 Aug 29;42(8):112994. doi: 10.1016/j.celrep.2023.112994. Epub 2023 Aug 22.

Authors

Hyo Lee¹, Aimee J Aylward¹, Richard V Pearse 2nd¹, Alexandra M Lish¹, Yi-Chen Hsieh¹, Zachary M Augur¹, Courtney R Benoit¹, Vicky Chou¹, Allison Knupp², Cheryl Pan¹, Srilakshmi Goberdhan¹, Duc M Duong³, Nicholas T Seyfried³, David A Bennett⁴, Mariko F Taga⁵, Kevin Huynh⁶, Matthias Arnold⁷, Peter J Meikle⁶, Philip L De Jager⁵, Vilas Menon⁵, Jessica E Young², Tracy L Young-Pearse⁸

Affiliations

¹ Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
² Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
³ Department of Biochemistry, Emory School of Medicine, Atlanta, GA, USA.
⁴ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
⁵ 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.
⁶ Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Bundoora, VIC, Australia.
⁷ 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.
⁸ 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.

Abstract

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.

Keywords: APOE; Alzheimer's; CLU; CP: Neuroscience; SMAD; SORL1; TGFbeta; amyloid; endolysosomal; retromer; tau.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Alzheimer Disease* / genetics
Apolipoproteins E / genetics
Cell Growth Processes
Clusterin* / genetics
Humans
LDL-Receptor Related Proteins / genetics
Membrane Transport Proteins
Neurons

Substances

Clusterin
Apolipoproteins E
SORL1 protein, human
LDL-Receptor Related Proteins
Membrane Transport Proteins
CLU protein, human

Abstract

Publication types

MeSH terms

Substances

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