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bioRxiv · 10.1101/2021.03.10.434768

Aβ promotes amyloidogenic processing of APP through a Go/Gβγ signaling

Antonino, M.·Marmo, P.·Freites, C. L.·Quassollo, G. E.·Sanchez, M. F.·Lorenzo, A.·Bignante, E. A.
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Abstract

Alzheimers disease (AD) is characterized by a cognitive impairment associated to amyloid beta (A{beta}) aggregation and deposition in the brain. A{beta} is generated by sequential cleavage of the amyloid precursor protein (APP) by {beta}-site APP cleaving enzyme 1 (BACE1) and {gamma}-secretase complex. The mechanisms that underlie exacerbated production of A{beta}, favoring its deposition in the brain, is largely unknown. In vitro studies have shown that A{beta} aggregates trigger enhanced production of A{beta} by a yet non described mechanism. Here, we show that in different cell types, including human neurons derived from induced pluripotent stem cells (iPSC), oligomers and fibrils of A{beta} enhance the convergence and interaction of APP and BACE1 in endosomal compartments. We demonstrated a key role of A{beta}-APP/Go/G{beta}{gamma} signaling on the amyloidogenic processing of APP. We show that APP mutants with impaired capacity to bind A{beta} or to activate Go protein, are unable to exacerbate APP and BACE1 colocalization in the presence of A{beta}. Moreover, pharmacological inhibition of G{beta}{gamma} subunits signaling with gallein, abrogate A{beta}-dependent interaction of APP and BACE1 in endosomes preventing {beta}-processing of APP. Collectively, these findings uncover a feed-forward mechanism of amyloidogenesis that might contribute to A{beta} pathology in early stages of AD and suggest that gallein might have clinical relevance.

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Antonino, M., Marmo, P., Freites, C. L., Quassollo, G. E., Sanchez, M. F., Lorenzo, A., Bignante, E. A.. 2021-03-11. Aβ promotes amyloidogenic processing of APP through a Go/Gβγ signaling. https://doi.org/10.1101/2021.03.10.434768

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