Abeta ASSEMBLIES PROMOTES AMYLOIDOGENIC PROCESSING OF APP AND INTRACELLULAR ACCUMULATION OF Abeta46;42 THROUGH Go/Gbeta-gamma SIGNALING.

ANTONINO, MAGDALENA; MARMO, PAULA; FREITES, LEANDRO; QUASSOLLO, GONZALO; SÁNCHEZ, MARÍA FLORENCIA; ALFREDO LORENZO; BIGNANTE, ELENA ANAHI

Frontiers in Cell and Developmental Biology

Frontiers Editorial

Lugar: Lausanne; Año: 2022

Alzheimer’s disease (AD) is characterized by the deposition of aggregated species ofamyloid 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 byβ-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 andthe development of AD. In vitro studies have demonstrated that Aβ assemblies spark afeed-forward loop heightening Aβ production. However, the underlying mechanismremains unknown. Here, we show that oligomers and fibrils of Aβ enhancecolocalization and physical interaction of APP and BACE1 in recycling endosomes ofhuman neurons derived from induced pluripotent stem cells and other cell types, whichleads to exacerbated amyloidogenic processing of APP and intracellular accumulation ofAβ42. In cells that are overexpressing the mutant forms of APP which are unable to bind Aβor to activate Go protein, we have found that treatment with aggregated Aβ fails to increasecolocalization of APP with BACE1 indicating that Aβ-APP/Go signaling is involved in thisprocess. Moreover, inhibition of Gβγ subunit signaling with βARKct or gallein prevents Aβ-dependent interaction of APP and BACE1 in endosomes, β-processing of APP, andintracellular accumulation of Aβ42. Collectively, our findings uncover a signalingmechanism leading to a feed-forward loop of amyloidogenesis that might contribute toAβ pathology in the early stages of AD and suggest that gallein could have therapeuticpotential.