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Lee, H.* ; Aylward, A.J.* ; Pearse, R.V.* ; Lish, A.M.* ; Hsieh, Y.C.* ; Augur, Z.M.* ; Benoit, C.R.* ; Chou, V.* ; Knupp, A.* ; Pan, C.* ; Goberdhan, S.* ; Duong, D.M.* ; Seyfried, N.T.* ; Bennett, D.A.* ; Taga, M.F.* ; Huynh, K.* ; Arnold, M. ; Meikle, P.J.* ; de Jager, P.L.* ; Menon, V.* ; Young, J.E.* ; Young-Pearse, T.L.*

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

Cell Rep. 42:112994 (2023)
Postprint DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Apoe ; Alzheimer's ; Clu ; Cp: Neuroscience ; Smad ; Sorl1 ; Tgfbeta ; Amyloid ; Endolysosomal ; Retromer ; Tau; Apolipoprotein-e; Amyloid-beta; Lr11/sorla Expression; Receptor Lr11; Association; Sorla/lr11; Mutations; Retromer; Biology; Model
Language english
Publication Year 2023
HGF-reported in Year 2023
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Journal Cell Reports
Quellenangaben Volume: 42, Issue: 8, Pages: , Article Number: 112994 Supplement: ,
Publisher Cell Press
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Computational Biology (ICB)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-503891-001
Grants NIH
DOI 10.1016/j.celrep.2023.112994
WOS ID 001076571700001
Scopus ID 85169503618
PubMed ID 37611586
Erfassungsdatum 2023-10-06
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