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

ABSTRACT: SORL1 is strongly implicated in the pathogenesis of Alzheimer’s disease (AD) through human genetic studies that point to an association of reduced SORL1 levels with higher risk for AD. To interrogate the role(s) of SORL1 in human brain cells, SORL1 null iPSCs were generated, followed by differentiation to neuron, astrocyte, microglial, and endothelial cell fates. Loss of SORL1 led to alterations in both overlapping and distinct pathways across cell types, with the greatest effects in neurons and astrocytes. Intriguingly, SORL1 loss led to a dramatic neuron-specific reduction in APOE and CLU levels, an increase in the accumulation of lipid droplets and altered lipid profiles. Pathway analysis implicated intracellular transport pathways and TGF-β/SMAD signaling in the function of SORL1 in neurons. Enhancement of retromer-mediated trafficking and autophagy rescued tau phenotypes observed in SORL1 null neurons but did not rescue APOE levels. However, stimulation and inhibition of SMAD signaling in neurons modulated APOE RNA levels in a SORL1-dependent manner. Further, analyses of iPSCs derived from a human aging cohort revealed a neuron-specific linear correlation between SORL1 and APOE RNA and protein levels, a finding validated in human post-mortem brain. These studies provide a mechanistic link between two of the strongest genetic risk factors for AD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE238013 | GEO | 2023/07/24

REPOSITORIES: GEO

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SORL1 regulates APOE and CLU levels in human neurons

Project description:SORL1 is implicated in the pathogenesis of Alzheimer’s disease (AD) through genetic studies. To interrogate the role(s) of SORL1 in human brain cells, SORL1 null iPSCs are 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 APOE and CLU and altered lipid profiles. Enhancement of retromer-mediated trafficking rescues tau phenotypes observed in SORL1 null neurons but does not rescue APOE levels. Pathway analyses implicate TGF-β/SMAD signaling in SORL1 function, and modulating SMAD signaling in neurons alters APOE RNA levels in a SORL1-dependent manner. Analyses of iPSCs derived from a large cohort reveal a neuron-specific association between SORL1, APOE, and CLU levels, a finding validated in post-mortem brain. These studies provide a mechanistic link between strong genetic risk factors for AD.

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

Project description:Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer’s disease risk gene SORL1

| PRJNA997371 | ENA

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Project description:Induced pluripotent stem cell (iPSC) disease models have been generated for a number of diseases, and some have shown their potential utilization for pathological and drug toxicological evaluations. We have generated two hiPSC clones from a non-familial Alzheimer’s patient (AD-iPSCs), which expressed typical undifferentiated markers and fulfilled standard pluripotency assays. Genome-wide microarray analysis revealed that AD-iPSCs are highly similar to control hiPSCs and hESCs, albeit with some noticeable differences in several genes: DNAJC15, GRPR, NAIP and SNORD116-18. Several other biomarkers were differentially expressed in AD-iPSC clones, which were implicated in memory impairment and AD. Furthermore, well characterized familial AD-associated genes (APP, PSEN1, PSEN2) and non-familial (A2M, APOE, GAP43, MAOA, MPO, PLAT, PLAU, SORL1, SNCA) exhibited different expression patterns but were largely reset upon reprogramming into a pluripotent state. Overall, hiPSCs can be good candidates for AD modeling and may represent an in vitro alternative to studying disease mechanisms and drug discovery/toxicology studies.

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