Grb2-mediated alteration in the trafficking of AbetaPP: insights from Grb2-AICD interaction

The amyloid-beta protein precursor (AbetaPP) is processed by various proteases located along the endosomal lysosomal pathway and any alteration in its trafficking would be important in the pathogenesis of Alzheimer's disease (AD). Our current study is based on the clinical evidence that an AbetaPP intracellular domain (AICD) "adaptor" protein, growth factor receptor protein binding protein 2 (Grb2), gets concentrated in neuronal cell bodies in AD patients. Here we show that both endogenous and exogenously transfected Grb2 interact with AbetaPP in Neuro 2A cells. Endogenous Grb2 partially co-localizes to late endosomal compartments along with AbetaPP and AICD. Increase in the concentration of Grb2 confines it in enlarged late endosomes leading to more sequestration of AbetaPP and AICD within these compartments. This confinement of AbetaPP due to Grb2 overexpression affects its turnover by inhibiting its release via exosomal vesicles. As a consequence, the level of intracellular AbetaPP and AICD increases. The effect of Grb2 overexpression has been verified by knocking down Grb2 as well as by overexpressing Grb2 in Grb2 knocked down cells. Having established the Grb2-mediated trafficking of AICD and its impairment, the significance of its consequence has now become apparent in the downstream events of AD pathogenesis.