The Impact of APP on Alzheimer-like Pathogenesis and Gene Expression in Down Syndrome iPSC-Derived Neurons.
Stem Cell Reports
; 11(1): 32-42, 2018 07 10.
Article
em En
| MEDLINE
| ID: mdl-29861166
ABSTRACT
Early-onset Alzheimer disease (AD)-like pathology in Down syndrome is commonly attributed to an increased dosage of the amyloid precursor protein (APP) gene. To test this in an isogenic human model, we deleted the supernumerary copy of the APP gene in trisomic Down syndrome induced pluripotent stem cells or upregulated APP expression in euploid human pluripotent stem cells using CRISPRa. Cortical neuronal differentiation shows that an increased APP gene dosage is responsible for increased ß-amyloid production, altered Aß42/40 ratio, and deposition of the pyroglutamate (E3)-containing amyloid aggregates, but not for several tau-related AD phenotypes or increased apoptosis. Transcriptome comparisons demonstrate that APP has a widespread and temporally modulated impact on neuronal gene expression. Collectively, these data reveal an important role for APP in the amyloidogenic aspects of AD but challenge the idea that increased APP levels are solely responsible for increasing specific phosphorylated forms of tau or enhanced neuronal cell death in Down syndrome-associated AD pathogenesis.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Expressão Gênica
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Precursor de Proteína beta-Amiloide
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Síndrome de Down
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Células-Tronco Pluripotentes Induzidas
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Doença de Alzheimer
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Neurônios
Tipo de estudo:
Etiology_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article