Abeta Assemblies Promote Amyloidogenic Processing of APP and Intracellular Accumulation of Abeta42 Through Go/Gbeta-gamma Signaling

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

Frontiers Cell and Develomental Biology

Frontiers Cell and Developmental Biology Editorial

Lugar: Lausana; Año: 2022 vol. 10

Alzheimer ́s disease (AD) is characterized by deposition of aggregated species of amyloid beta in the brain, which leads to progressive cognitive deficits and dementia. Abeta is generated by the successive cleavage of the amyloid precursor protein (APP), first by beta-site APP cleaving enzyme 1 (BACE1) and subsequently by the gamma-secretase complex. Conditions that enhance Abeta generation or reduce its clearance predispose to Abeta aggregation and the development of AD. In vitro studies have demonstrated that Abeta assemblies spark a feedforward loop heightening Abeta production. However, the underlying mechanism remains unknown. Here, we show that oligomers and fibrils of Abeta 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 Abeta42. In cells overexpressing mutant forms of APP that are unable to bind Abeta or to activate Go protein, we have found that treatment with aggregated Abeta fail to increase colocalization of APP with BACE1 indicating that Abeta-APP/Go signaling is involved in this process. Moreover, inhibition of Gbetagamma subunit signaling with bARKct or gallein, prevent Abeta-dependent interaction of APP and BACE1 in endosomes, beta-processing of APP and intracellular accumulation of Abeta42. Collectively, our findings uncover a signaling mechanism leading to a feedforward loop of amyloidogenesis that might contribute to Abeta pathology in early stages of AD and suggest that gallein could have therapeutic potential.