TY - JOUR
KW - APOE
KW - Alzheimer's
KW - CLU
KW - SMAD
KW - SORL1
KW - TGFbeta
KW - amyloid
KW - endolysosomal
KW - retromer
KW - tau
AU - Hyo Lee
AU - Aimee J. Aylward
AU - Richard V. Pearse
AU - Alexandra M. Lish
AU - Yi-Chen Hsieh
AU - Zachary M. Augur
AU - Courtney R. Benoit
AU - Vicky Chou
AU - Allison Knupp
AU - Cheryl Pan
AU - Srilakshmi Goberdhan
AU - Duc M. Duong
AU - Nicholas T. Seyfried
AU - David A. Bennett
AU - Mariko F. Taga
AU - Kevin Huynh
AU - Matthias Arnold
AU - Peter J. Meikle
AU - Philip L. De Jager
AU - Vilas Menon
AU - Jessica E. Young
AU - Tracy L. Young-Pearse
AB - 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.
BT - Cell Reports
DA - 2023-08-29
DO - 10.1016/j.celrep.2023.112994
IS - 8
N2 - 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.
PY - 2023
EP - 112994
T2 - Cell Reports
TI - Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer’s disease risk gene SORL1
UR - https://www.sciencedirect.com/science/article/pii/S2211124723010057
VL - 42
Y2 - 2023-09-15
SN - 2211-1247
ER -