Modelling APOE É3/4 allele-associated sporadic Alzheimer's disease in an induced neuron.
Brain
; 140(8): 2193-2209, 2017 Aug 01.
Article
em En
| MEDLINE
| ID: mdl-28899010
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) É3/4 allele. We show that mouse and human induced neurons overexpressing mutant amyloid precursor protein in the background of APOE É3/4 allele exhibit altered amyloid precursor protein (APP) processing, abnormally increased production of amyloid-ß42 and hyperphosphorylation of tau. Importantly, we demonstrate that APOE É3/4 patient induced neuron culture models can faithfully recapitulate molecular signatures seen in APOE É3/4-associated sporadic Alzheimer's disease patients. Moreover, analysis of the gene network derived from APOE É3/4 patient induced neurons reveals a strong interaction between APOE É3/4 and another Alzheimer's disease risk factor, desmoglein 2 (DSG2). Knockdown of DSG2 in APOE É3/4 induced neurons effectively rescued defective APP processing, demonstrating the functional importance of this interaction. These data provide a direct connection between APOE É3/4 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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Alelos
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Apolipoproteína E3
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Apolipoproteína E4
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Doença de Alzheimer
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Neurônios
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Brain
Ano de publicação:
2017
Tipo de documento:
Article