Alzheimer's disease-related loss of Pin1 function influences the intracellular localization and the processing of AβPP.

Increased amyloidogenic processing of the amyloid-beta protein precursor (A beta PP) is a characteristic of Alzheimer's disease (AD). We previously observed that the prolyl isomerase Pin1, which is down-regulated in AD, regulates A beta PP conformation accelerating cis/trans isomerization of the phospho-Thr668-Pro669 peptide bond, and that Pin1 knockout in mice increases the amyloidogenic processing of A beta PP, although the underlying mechanism is still unknown. Since the intracellular localization of A beta PP determines whether the processing will be amyloidogenic or non-amyloidogenic, here we addressed the question whether loss of Pin1 function affects the intracellular localization of A beta PP, influencing A beta PP processing. Using cellular models of Pin1 knockout and Pin1 knockdown, we have demonstrated that lowering Pin1 levels changed the intracellular localization and the processing of A beta PP. Under these conditions, less A beta PP was retained at the plasma membrane favoring the amyloidogenic processing, and the kinetics of A beta PP internalization increased as well as the nuclear trafficking of A beta PP C-terminal fragment AICD. In addition, A beta PPThr668Ala mutant, which cannot bind to Pin1 and retains more trans conformation, rescued the levels of A beta PP at the plasma membrane in Pin1 knockout cells. Thus, loss of Pin1 function contributes to amyloidogenic pathways, by facilitating both the removal of A beta PP from compartments where it is mostly non-amyloidogenic and its internalization to more amyloidogenic compartments. These data suggest that physiological levels of Pin1 are important to control the intracellular localization and metabolic fate of Thr668-phosphorylated A beta PP, and regulation of A beta PP conformation is especially important in pathologic conditions of A beta PP hyperphosphorylation and/or loss of Pin1 function, associated with AD.