@article{ee5288b1a99e44db957c3c53778619cd,
title = "Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer's disease risk gene SORL1",
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 = "Alzheimer's, amyloid, APOE, CLU, CP: Neuroscience, endolysosomal, retromer, SMAD, SORL1, tau, TGFbeta",
author = "Hyo Lee and Aylward, {Aimee J.} and Pearse, {Richard V.} and Lish, {Alexandra M.} and Hsieh, {Yi Chen} and Augur, {Zachary M.} and Benoit, {Courtney R.} and Vicky Chou and Allison Knupp and Cheryl Pan and Srilakshmi Goberdhan and Duong, {Duc M.} and Seyfried, {Nicholas T.} and Bennett, {David A.} and Taga, {Mariko F.} and Kevin Huynh and Matthias Arnold and Meikle, {Peter J.} and {De Jager}, {Philip L.} and Vilas Menon and Young, {Jessica E.} and Young-Pearse, {Tracy L.}",
note = "Funding Information: We thank the AMP-AD consortium for valuable feedback and data sharing (see also “Data and code availability”) and the NeuroTechnology Studio at Brigham and Women{\textquoteright}s Hospital for providing Zeiss LSM710 confocal instrument access and consultation on data acquisition and data analysis; iPSC NeuroHub at Brigham and Women{\textquoteright}s Hospital for technical assistance with iN differentiation; Saranna Fanning for providing reagents and guidance on lipid droplet analysis; Charles Jennings, Scott Small, and Gregory Petsko for manuscript feedback; Thomas Schwarz, Dennis Selkoe, and Francisco Quintana for their Dissertation Advisory Committee guidance; and to members of the Young-Pearse lab for their input. This work was supported by NIH grants F31AG063399 , U01AG072572 , U01AG061356 , U01AG061359 , RF1NS117446 , and R01AG055909 . Publisher Copyright: {\textcopyright} 2023 The Authors",
year = "2023",
month = aug,
day = "29",
doi = "10.1016/j.celrep.2023.112994",
language = "English",
volume = "42",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Elsevier",
number = "8",
}
