STUDY OF THE MECHANISM OF ENRICHMENT OF APP IN ENDOSOMES INDUCED BY Aβ AND ITS MODULATION BY Gβγ SIGNALING

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

Buenos Aires

Congreso; XXXVII Congreso Anual de la Sociedad Argentina de Investigación en Neurociencia (SAN); 2022

Sociedad Argentina de Investigación en Neurociencias

Alzheimer´s disease is characterized by the deposition of aggregated species of amyloid beta (Aβ) in the brain, which leads to progressive cognitive deficits and dementia. We recently found that Aβ assemblies, oligomers and fibrils, increase APP and BACE1 interaction in recycling endosomes of human neurons derived from iPSCs by a mechanism dependent of APP/Go/Gβγ signaling. Now, we are interested on deepen in the APP trafficking in the endo-lysosomal pathway in order to understand the mechanism underlying such effect. We found that Aβ induced an enrichment of APP in recycling endosomes at the expense of a decrement of its levels in lysosomes. This change in APP intracellular distribution is drive by Gβγ signaling. Moreover, we found that the changes on APP distribution correlate with an increase in its interaction with BACE1, also modulates by a Gβγ signaling. Together, these results suggest that Aβ pathological assemblies induce a re-direction of APP from its physiological route to lysosomes, to recycling endosomes which favors its encounter with BACE1. These finding elucidate the intracellular process which sustain the feed-forward mechanisms implicated in the amyloidogenesis induced by pathological assemblies of Aβ.