Peptidyl-prolyl Isomerase Pin1 as a Potential Target to Protect Synaptic Function in Preclinical Alzheimer's Disease (P1.236)

OBJECTIVE: To gain insight into the pathological role of Pin1 in conjunction with the three pathological hallmarks of Alzheimer’s disease (AD): β-amyloid (Aβ) plaques, hyperphosphorylated tau tangles, and synaptic loss. This investigation will also examine the role of Pin1 as a potential therapeutic target to prevent synaptic loss in preclinical AD induced by overactivity of NMDA receptors or oligomers of Aβ. BACKGROUND: Alzheimer’s disease (AD) is characterized by synaptic loss which correlates strongly with memory impairment. The loss of Pin1, a peptidyl-prolyl isomerase, increases the formation of plaques and tangles in preclinical AD. Pin1 also decides the fate of proteins through the ubiqutin proteasome system. Shank3 proteins are modified by ubiquitin and lost in AD. Shank3 proteins organize glutamate receptors in the postsynaptic density (PSD) and stimulate the formation of spines. Pin1 could play a pathological role in Shank protein loss and could be used as a therapeutic target for preventing synaptic loss in preclinical AD. DESIGN/METHODS: Human AD cortical tissues were used to identify the pathological changes of Pin1 in dendritic rafts and PSD by proteomics and western blot. To detect the pathological roles of Pin1 at the synapse, we utilized cultured cortical neurons from Pin1-knocked out mice, or the cultured neurons from wild-type mice treated with Pin1 inhibitor or Pin1 ShRNA. The synaptic proteins and ubiqutinated-proteins were analyzed; meanwhile, aberrant dendritic spines were detected by immunocytochemistry. RESULTS: The loss of Pin1 activity may modify PSD proteins by ubiquitin, such as Shank 3 in AD, leading to aberrant synapses, making the synapses more susceptible to the toxicity of Aβ oligomers and NMDA-receptor overactivity, and inhibiting synapse formation. CONCLUSIONS: The results indicate that Pin 1 protein may serve as a target for protecting synaptic function and for regulating synaptic regeneration in the preclinical stages of AD. Disclosure: Dr. Ong has nothing to disclose. Dr. Chow has nothing to disclose. Dr. Gong has nothing to disclose. Dr. Lippa has received personal compensation in an editorial capacity for Sage Publications. Dr. Lippa has received research support from Elan Corporation/Wyeth Pharmaceuticals, and UCB Pharma.