Cell-type-specific Regulation of APOE and CLU Levels in Human Neurons by the Alzheimer's Disease Risk Gene SORL1

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2023 Aug 23

PMID 37611586

Authors

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

Affiliations

Soon will be listed here.

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.

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