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Modelling APOE epsilon 3/4 allele-associated sporadic Alzheimer's disease in an induced neuron : Modelling APOE ϵ3/4 allele-associated sporadic Alzheimer's disease in an induced neuron
Cited 22 time in
Web of Science
Cited 23 time in Scopus
- Authors
- Issue Date
- 2017-08
- Publisher
- Oxford University Press
- Citation
- Brain, Vol.140 No.8, pp.2193-2209
- Abstract
- The recent generation of induced neurons by direct lineage conversion holds promise for in vitro modelling of sporadic Alzheimer's disease. Here, we report the generation of induced neuron-based model of sporadic Alzheimer's disease in mice and humans, and used this system to explore the pathogenic mechanisms resulting from the sporadic Alzheimer's disease risk factor apolipoprotein E (APOE) epsilon 3/4 allele. We show that mouse and human induced neurons overexpressing mutant amyloid precursor protein in the background of APOE epsilon 3/4 allele exhibit altered amyloid precursor protein (APP) processing, abnormally increased production of amyloid-beta(42) and hyperphosphorylation of tau. Importantly, we demonstrate that APOE epsilon 3/4 patient induced neuron culture models can faithfully recapitulate molecular signatures seen in APOE epsilon 3/4-associated sporadic Alzheimer's disease patients. Moreover, analysis of the gene network derived from APOE epsilon 3/4 patient induced neurons reveals a strong interaction between APOE epsilon 3/4 and another Alzheimer's disease risk factor, desmoglein 2 (DSG2). Knockdown of DSG2 in APOE epsilon 3/4 induced neurons effectively rescued defective APP processing, demonstrating the functional importance of this interaction. These data provide a direct connection between APOE epsilon 3/4 and another Alzheimer's disease susceptibility gene and demonstrate in proof of principle the utility of induced neuron-based modelling of Alzheimer's disease for therapeutic discovery.
- ISSN
- 0006-8950
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