Aβ assemblies promote amyloidogenic processing of APP and intracellular accumulation of Aβ42 through Go/Gβγ signaling

  • Alzheimer’s disease (AD) is characterized by the deposition of aggregated species of amyloid beta (Aβ) in the brain, which leads to progressive cognitive deficits and dementia. Aβ is generated by the successive cleavage of the amyloid precursor protein (APP), first by β-site APP cleaving enzyme 1 (BACE1) and subsequently by the γ-secretase complex. Those conditions which enhace or reduce its clearance predispose to Aβ aggregation and the development of AD. In vitro studies have demonstrated that Aβ assemblies spark a feed-forward loop heightening Aβ production. However, the underlying mechanism remains unknown. Here, we show that oligomers and fibrils of Aβ 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 Aβ42. In cells that are overexpressing the mutant forms of APP which are unable to bind Aβ or to activate Go protein, we have found that treatment with aggregated Aβ fails to increase colocalization of APP with BACE1 indicating that Aβ-APP/Go signaling is involved in this process. Moreover, inhibition of Gβγ subunit signaling with βARKct or gallein prevents Aβ-dependent interaction of APP and BACE1 in endosomes, β-processing of APP, and intracellular accumulation of Aβ42. Collectively, our findings uncover a signaling mechanism leading to a feed-forward loop of amyloidogenesis that might contribute to Aβ pathology in the early stages of AD and suggest that gallein could have therapeutic potential.

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Author:Magdalena AntoninoORCiD, Paula Marmo, Carlos Leandro FreitesORCiD, Gonzalo Emiliano QuassolloORCiD, María SánchezORCiDGND, Alfredo LorenzoORCiD, Elena Anahi BignanteORCiD
URN:urn:nbn:de:hebis:30:3-824881
DOI:https://doi.org/10.3389/fcell.2022.852738
ISSN:2296-634X
Parent Title (English):Frontiers in cell and developmental biology
Publisher:Frontiers Media
Place of publication:Lausanne
Document Type:Article
Language:English
Date of Publication (online):2022/04/04
Date of first Publication:2022/04/04
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2024/05/07
Tag:Alzheimer’s disease; BACE1; Gβγ subunit; amyloid beta; amyloid precursor protein; gallein; human neurons; iPSc
Volume:10
Issue:art. 852738
Article Number:852738
Page Number:16
First Page:1
Last Page:16
HeBIS-PPN:519209656
Institutes:Biochemie, Chemie und Pharmazie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International