Peptidyl-Prolyl Isomerase Pin1: A Common Therapeutic Target for Synaptic Dysfunction and Protein Misfolding in Alzheimer's Disease (SC02.008)

Objective: The Pin1 protein, a peptidyl-prolyl isomerase, facilitates proper folding of proteins. Loss of Pin1 in mice induces formation of misfolded beta-amyloid and hyperphosphorylated tau at dendritic rafts, which suggests that Pin1 may pathologically alter dendritic rafts and the post-synaptic density (PSD) in Alzheimer9s disease (AD). In this study, we observed Pin1 associations with synaptic proteins and compared Pin1 pathological changes in AD patients against controls. Background The structural basis for memory formation lies in the neuronal excitatory synapse. Unique to this synapse and underlying its function are integrated detergent-resistant dendritic rafts and PSD within the postsynaptic structure. The association of the pathological hallmarks of AD--misfolded oligomers of beta-amyloid and hyperphosphorylated tau--with these detergent-resistant microdomains may lead to synaptic dysfunction and loss. Design/Methods: Human cortices from 12 AD patients and 10 age-matched controls were prepared using a tissue extraction protocol, followed by SDS-PAGE, Western and Dot blot analyses. Mice cortical neurons were cultured and visualized using immunocytochemistry, immunoblot, and confocal microscopy. Results: We found that in AD, Pin1 proteins coincidently associated with NMDA receptor 1, Shank3 proteins, and misfolded proteins at dendritic rafts and the PSD. The protein levels of Pin1 were pathologically increased in dendritic rafts and decreased in the PSD of AD brains. In cultured neurons, Pin1 proteins co-localized with NMDA receptor 1 and Shank3, and dendritic spines degenerated after Pin1 activity was blocked. Conclusions: Our findings suggest that pathological distribution and loss of Pin1 at the synapse may have a direct effect on phosphorylation and homeostasis of proteins beside beta-amyloid and hyperphosphorylated tau in AD development. Pin1 may prove to be a common therapeutic target for both the treatment of synaptic dysfunction and misfolding of beta-amyloid and phosphorylated tau at synapses in early stages of AD. Disclosure: Dr. Chow has nothing to disclose. Dr. Tsai has nothing to disclose. Dr. Lippa has received personal compensation in an editorial capacity for Sage Publications.Dr. Lippa has received research support from UCB Pharma and DUCOM. Dr. Gong has nothing to disclose.