Article

Alzheimer's Disease-Related Loss of Pin1 Function Influences the Intracellular Localization and the Processing of A beta PP

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Journal of Alzheimer's disease: JAD (Impact Factor: 3.61). 03/2012; 30(2):277-97. DOI: 10.3233/JAD-2012-111259
Source: PubMed

ABSTRACT Increased amyloidogenic processing of the amyloid-β protein precursor (AβPP) is a characteristic of Alzheimer's disease (AD). We previously observed that the prolyl isomerase Pin1, which is down-regulated in AD, regulates AβPP conformation accelerating cis/trans isomerization of the phospho-Thr668-Pro669 peptide bond, and that Pin1 knockout in mice increases the amyloidogenic processing of AβPP, although the underlying mechanism is still unknown. Since the intracellular localization of AβPP 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 AβPP, influencing AβPP 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 AβPP. Under these conditions, less AβPP was retained at the plasma membrane favoring the amyloidogenic processing, and the kinetics of AβPP internalization increased as well as the nuclear trafficking of AβPP C-terminal fragment AICD. In addition, AβPPThr668Ala mutant, which cannot bind to Pin1 and retains more trans conformation, rescued the levels of AβPP at the plasma membrane in Pin1 knockout cells. Thus, loss of Pin1 function contributes to amyloidogenic pathways, by facilitating both the removal of AβPP 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 AβPP, and regulation of AβPP conformation is especially important in pathologic conditions of AβPP hyperphosphorylation and/or loss of Pin1 function, associated with AD.

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