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

ABSTRACT Alzheimer’s disease (AD) is characterized by a cognitive impairment associated to amyloid beta (Aβ) aggregation and deposition in the brain. Aβ is generated by sequential cleavage of the amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase complex. The mechanisms that underlie exacerbated production of Aβ, favoring its deposition in the brain, is largely unknown. In vitro studies have shown that Aβ aggregates trigger enhanced production of Aβ 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 Aβ enhance the convergence and interaction of APP and BACE1 in endosomal compartments. We demonstrated a key role of Aβ-APP/Go/Gβγ signaling on the amyloidogenic processing of APP. We show that APP mutants with impaired capacity to bind Aβ or to activate Go protein, are unable to exacerbate APP and BACE1 colocalization in the presence of Aβ. Moreover, pharmacological inhibition of Gβγ subunits signaling with gallein, abrogate Aβ-dependent interaction of APP and BACE1 in endosomes preventing β-processing of APP. Collectively, these findings uncover a feed-forward mechanism of amyloidogenesis that might contribute to Aβ pathology in early stages of AD and suggest that gallein might have clinical relevance.