DISTRIBUTION OF APP IN ENDO-LYSOSOMAL SYSTEM INDUCED BY Aβ IS MODULATED BY Gβγ SIGNALING

ANTONINO MAGDALENA; ALMIRON ROMINA SOLEDAD; MARMO PAULA; LORENZO ALFREDO; BIGNANTE ELENA ANAHI

Amsterdam

Congreso; Alzheimer?s Association international Conference, 2023; 2023

Alzheimer`s Association

Abstract Text:Background:Alzheimer´s disease is characterized by the deposition of aggregated species of amyloidbeta (Aβ) in the brain, which leads to progressive cognitive deficits and dementia. We recently foundthat Aβ assemblies, oligomers and fibrils, increase APP and BACE1 interaction in recycling endosomesand accumulation of intracellular Aβ42 in human neurons derived from iPSCs by a mechanismdependent of APP/Go/Gβγ signaling (Antonino et al 2022, DOI: 10.3389/fcell.2022.852738). Now, weare interested on deepen in the APP trafficking in the endo-lysosomal pathway in order to understandthe mechanism underlying such effect.Method:N2a and human neurons derived from iPSc cultures were transfected with fluorescentlytagged proteins (APP-YFP, BACE-CH, Rab11-RFP, LAMP1-CH, Rab7-CH, APP-VN, BACE-VC).Cultures were treated with vehicle or the Gβγ inhibitor gallein and 30 minutes later with vehicle or 1 μMof Aβ oligomeric or fibrillar. After 24 h of treatment quantitative colocalization analysis and bimolecularfluorescence complementation assays were performed.Result:We found that Aβ induced an enrichment of APP in recycling endosomes at the expense of adecrement of its levels in lysosomes. This change in APP intracellular distribution is drive by Gβγsignaling. Moreover, we found that the changes on APP distribution correlate with an increase in itsinteraction with BACE1 and with an increase in the number of recycling endosomes, both eventsmodulated by Gβγ signaling (Figure 1,2).Conclusion:Together, these results suggest that Aβ pathological assemblies induce a re-direction ofAPP from its physiological route to lysosomes, to recycling endosomes which favors its encounter withBACE1 and its amyloidogenic processing. These finding elucidate the intracellular process whichsustain the feed-forward mechanisms implicated in the amyloidogenesis induced by pathologicalassemblies of Aβ.