Role of Ab/APP interaction in the increase of APP and BACE 1 convergence induced by Ab

MUSSO, JULIANA; ANTONINO, MAGDALENA; LORENZO, ALFREDO; FREITES, LEANDRO

Córdoba

Congreso; XXXIII Congress of the Argentine Society for Research in Neuroscience; 2019

Sociedad Argentina de Investigación en Neurociencias (SAN)

Alzheimer's disease (AD) is the most prevalent form of dementia linked to aging and its cause is related to the accumulation of the beta amyloid (Aβ) peptide in brain. Aβ derives from sequential cleavage of amyloid precursor protein (APP) by BACE 1 and γ-secretase. Both, APP and BACE 1, are transmembrane proteins which present a dynamic intracellular traffic. Moreover, the site of convergence of both proteins and its modulation is yet unclear. Exist some evidence that suggest that Aβ is capable of induce its own production. In this study, we try to delineate, using confocal microscopy and quantitative colocalization analysis, which is the basal distribution of APP and BACE 1 in HELA cells and how this arrangement is affected by Aβ treatment. We saw that initially APP and BACE 1 have a low colocalization which is increased after a 24 hs treatment withAβ 10 uM as result of a re-distribution of APP and BACE 1 in recycling endosome. Also we verified that this effect is a consequence of the Aβ/APP interaction in such a way that when it is expressed a deletioned APP that lacks binding domain to Aβ (APPΔβ), the increase of convergence of APP and BACE 1 induced by Aβ is avoided. Finally, we saw that the increase in the encounter between APP and BACE 1 after Aβ treatment is the consequence of the activation of a signaling pathway mediated by APP/Go/βγ proteins since gallein, a specific βγ inhibitor, is capable to preclude it.