Cited 189 time in webofscience Cited 221 time in scopus

APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types

Title
APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types
Authors
Lin, Y.-T.Seo, JinsooGao, F.Feldman, H.M.Wen, H.-L.Penney, J.Cam, H.P.Gjoneska, E.Raja, W.K.Cheng, J.Rueda, R.Kritskiy, O.Abdurrob, F.Peng, Z.Milo, B.Yu, C.J.Elmsaouri, S.Dey, D.Ko, T.Yankner, B.A.Tsai, L.-H.
DGIST Authors
Seo, Jinsoo
Issue Date
2018-06
Citation
Neuron, 98(6), 1141-1154
Type
Article
Article Type
Article
Keywords
APOEAlzheimer’s diseaseiPSCCRISPR/Cas9Aβ uptakecerebral organoidscholesterolearly endosomesimmune response
ISSN
0896-6273
Abstract
The apolipoprotein E4 (APOE4) variant is the single greatest genetic risk factor for sporadic Alzheimer's disease (sAD). However, the cell-type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to examine APOE4 effects on human brain cell types. Transcriptional profiling identified hundreds of differentially expressed genes in each cell type, with the most affected involving synaptic function (neurons), lipid metabolism (astrocytes), and immune response (microglia-like cells). APOE4 neurons exhibited increased synapse number and elevated Aβ42 secretion relative to isogenic APOE3 cells while APOE4 astrocytes displayed impaired Aβ uptake and cholesterol accumulation. Notably, APOE4 microglia-like cells exhibited altered morphologies, which correlated with reduced Aβ phagocytosis. Consistently, converting APOE4 to APOE3 in brain cell types from sAD iPSCs was sufficient to attenuate multiple AD-related pathologies. Our study establishes a reference for human cell-type-specific changes associated with the APOE4 variant. By generating and characterizing isogenic APOE3- or APOE4-carrying human brain cell types, Lin et al. show that the APOE4 variant can lead to extensive gene expression alterations, and multiple cellular phenotypes potentially related to AD pathogenesis, in neurons, astrocytes, and microglia. © 2018 Elsevier Inc.
URI
http://hdl.handle.net/20.500.11750/6589
DOI
10.1016/j.neuron.2018.05.008
Publisher
Cell Press
Related Researcher
  • Author Seo, Jinsoo Laboratory of Aging Brain
  • Research Interests iPSC; Alzheimer's disease; Neurodegeneration; Synapse; Neuroscience
Files:
There are no files associated with this item.
Collection:
Department of Brain and Cognitive SciencesLaboratory of Aging Brain1. Journal Articles


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