Aß Assemblies Promote Amyloidogenic Processing of APP and Intracellular Accumulation of Aß42 Through Go/Gßγ Signaling.
Front Cell Dev Biol
; 10: 852738, 2022.
Article
em En
| MEDLINE
| ID: mdl-35445022
Alzheimer's disease (AD) is characterized by the deposition of aggregated species of amyloid beta (Aß) in the brain, which leads to progressive cognitive deficits and dementia. Aß is generated by the successive cleavage of the amyloid precursor protein (APP), first by ß-site APP cleaving enzyme 1 (BACE1) and subsequently by the γ-secretase complex. Those conditions which enhace or reduce its clearance predispose to Aß aggregation and the development of AD. In vitro studies have demonstrated that Aß assemblies spark a feed-forward loop heightening Aß production. However, the underlying mechanism remains unknown. Here, we show that oligomers and fibrils of Aß enhance colocalization and physical interaction of APP and BACE1 in recycling endosomes of human neurons derived from induced pluripotent stem cells and other cell types, which leads to exacerbated amyloidogenic processing of APP and intracellular accumulation of Aß42. In cells that are overexpressing the mutant forms of APP which are unable to bind Aß or to activate Go protein, we have found that treatment with aggregated Aß fails to increase colocalization of APP with BACE1 indicating that Aß-APP/Go signaling is involved in this process. Moreover, inhibition of Gßγ subunit signaling with ßARKct or gallein prevents Aß-dependent interaction of APP and BACE1 in endosomes, ß-processing of APP, and intracellular accumulation of Aß42. Collectively, our findings uncover a signaling mechanism leading to a feed-forward loop of amyloidogenesis that might contribute to Aß pathology in the early stages of AD and suggest that gallein could have therapeutic potential.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Front Cell Dev Biol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Argentina
País de publicação:
Suíça