Abeta INDUCES AMYLOIDOGENESIS IN HUMAN NEURONS THROUGH Gbetagamma SUBUNIT SIGNALING

ANTONINO, MAGDALENA; MARMO, PAULA; LORENZO, ALFREDO; BIGNANTE, ELENA ANAHI

Cordoba

Congreso; XXXVI Congreso Anual de la Sociedad Argentina de investigación en Neurociencia (SAN); 2021

Sociedad Argentina de Neurociencia

Aggregation and progressive deposition of amyloid beta (Abeta) is a fundamental event in the pathogenesis of Alzheimer’s disease (AD). The cleavage of the amyloid precursor protein (APP) by BACE1 is the most critical event in amyloidogenesis, although the mechanism and the intracellular compartment where this event occurs are still discussed. It has been reported that Abeta is capable of inducing its own production, but the mechanism is yet unclear. We hypothesized that the interaction of Abeta aggregates with APP, acting as its receptor, activates a signaling pathway mediated by Go/betagamma that enhance the intracellular convergence of APP and BACE1 in amyloidogenic compartments, particularly in recycling endosomes (RE), favoring Abeta production.Overexpressing a system of bimolecular fluorescence complementation (BiFC: APP-Vn and BACE1-Vc) in human neurons, we found that treatment with Abeta oligomeric (o-Abeta) increased BiFC intensity, effect that was abrogated by gallein, a pharmacological inhibitor of betagamma signaling. Moreover, o-Abeta enhanced the BiFC intensity in Rab11-positive RE, effect that was avoided by gallein. Also, we found that Abeta treatments with fibrillar Abeta (fAbeta) augmented amount of beta-CTF and intracellular Abeta, and gallein abolished this increment.