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

lzheimer’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 overexpressi