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APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids
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APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids
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Journal Article
APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids
2020
Overview
APOE4
is the strongest genetic risk factor associated with late-onset Alzheimer’s disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with
APOE
ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying
APOE
ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids,
APOE4
exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of
APOE4
to
APOE3
attenuates the
APOE4
-related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates
APOE4
-related phenotypes and suggests
APOE4
-related degenerative pathways contributing to AD pathogenesis.
APOE4
is a strong genetic risk factor for late-onset Alzheimer’s disease. Here, the authors show that
APOE4
is associated with AD features in hiPSCs-derived cerebral organoids. Isogenic conversion of
APOE4
to
APOE3
attenuates the AD-associated phenotype.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/106
/ Alzheimer Disease - genetics
/ Alzheimer Disease - metabolism
/ Apolipoprotein E3 - genetics
/ Apolipoprotein E3 - metabolism
/ Apolipoprotein E4 - genetics
/ Genotype
/ Humanities and Social Sciences
/ Humans
/ Induced Pluripotent Stem Cells - metabolism
/ Inhibitory postsynaptic potentials
/ Patients
/ RNA
/ Science
/ Synapses
