CHOLESTEROL ENDO-LYSOSOMAL DISTRIBUTION RESEMBLING NEURONAL AGING FAVORS ALZHEIMER’S DISEASE LINKED PROCESSES

MARTINEZ NAVARRO, ROSARIO; ALMIRON, ROMINA; ANTONINO, MAGDALENA; MARTIN, MAURICIO; BIGNANTE, ELENA ANAHI

Rosario

Congreso; Congreso Anual de la Sociedad Argentina de Investigaciones en Bioquímica y Biología Molecular; 2023

Sociedad Argentina de Investigaciones en Bioquímica y Biología Molecular

Aging is the main risk factor for the Alzheimer’s disease (AD) occurrence. It was reported thataging of hippocampal neurons is associated with a decrease in membrane cholesterol.Taking into account that cholesterol levels in the membrane affect multiple molecular processes,in this work we study how the redistribution of cholesterol emulating aging, affects the interactionof protein linked to AD. We particularly analyzed the effect of lowering cholesterol levels onevents related to the amyloid precursor protein (APP) focusing in both: its role as Aβ precursorinteracting with BACE1, as well as in its role as a membrane receptor analyzing its degree ofhomodimerization.One of the mechanisms that underlie the reduction of cholesterol in neuronal membranes is adecline in the levels of the NPC1 protein which is involved in the release of cholesterol fromlysosomes following its endocytosis. We used the compound U18666a to induce re-distribution ofcholesterol, emulating aging, and analyzed the interaction between APP and BACE1 and thedimerization of APP by bimolecular fluorescence complementation.We found that U18666a treatment increased the degree of APP dimerization, which could berelated to activation of pathological signal transduction downstream.Likewise, we observed that U18666a treatment incremented the interaction between APP andBACE1, an effect that was avoided by incubation with the endocannabinoid anandamide whichrestores cholesterol efflux from lysosomes.In conclusion, the reduction on cholesterol levels on neurons favors events linked to AD sinceinduces: an increment in APP/BACE1 interaction which could relate to an increment on APPamyloidogenic processing and Aβ production; and also promotes APP dimerization which arelinked to augmented APP signaling and amyloidogenesis.