02492nas a2200517   4500000000100000008004100001260001500042653000900057653001600066653000800082653000900090653001000099653001200109653001200121653001800133653001300151653000800164100001200172700002100184700002200205700002200227700001800249700002100267700002300288700001500311700001800326700001500344700002500359700001700384700002500401700002100426700001900447700001600466700002000482700002000502700002300522700001600545700002100561700002600582245011900608856007200727300001100799490000700810520114300817022001401960       2023                            d  c2023-08-2910aAPOE10aAlzheimer's10aCLU10aSMAD10aSORL110aTGFbeta10aamyloid10aendolysosomal10aretromer10atau1 aHyo Lee1 aAimee J. Aylward1 aRichard V. Pearse1 aAlexandra M. Lish1 aYi-Chen Hsieh1 aZachary M. Augur1 aCourtney R. Benoit1 aVicky Chou1 aAllison Knupp1 aCheryl Pan1 aSrilakshmi Goberdhan1 aDuc M. Duong1 aNicholas T. Seyfried1 aDavid A. Bennett1 aMariko F. Taga1 aKevin Huynh1 aMatthias Arnold1 aPeter J. Meikle1 aPhilip L. De Jager1 aVilas Menon1 aJessica E. Young1 aTracy L. Young-Pearse00aCell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer’s disease risk gene SORL1  uhttps://www.sciencedirect.com/science/article/pii/S2211124723010057  a1129940 v423 aSORL1 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.  a2211-1247