A beta Assemblies Promote Amyloidogenic Processing of APP and Intracellular Accumulation of A beta 42 Through Go/G beta gamma Signaling

Alzheimer's disease (AD) is characterized by the deposition of aggregated species of amyloid beta (A beta) in the brain, which leads to progressive cognitive deficits and dementia. A beta 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. Those conditions which enhace or reduce its clearance predispose to A beta aggregation and the development of AD. In vitro studies have demonstrated that A beta assemblies spark a feed-forward loop heightening A beta production. However, the underlying mechanism remains unknown. Here, we show that oligomers and fibrils of A beta 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 A beta 42. In cells that are overexpressing the mutant forms of APP which are unable to bind A beta or to activate Go protein, we have found that treatment with aggregated A beta fails to increase colocalization of APP with BACE1 indicating that A beta-APP/Go signaling is involved in this process. Moreover, inhibition of G beta gamma subunit signaling with beta ARKct or gallein prevents A beta-dependent interaction of APP and BACE1 in endosomes, beta-processing of APP, and intracellular accumulation of A beta 42. Collectively, our findings uncover a signaling mechanism leading to a feed-forward loop of amyloidogenesis that might contribute to A beta pathology in the early stages of AD and suggest that gallein could have therapeutic potential.