Role of Pin1 and Presenilin-1 Interaction In Vivo

Project Summary

Alzheimer's disease is the most common form of dementia and its pathological hallmarks are tangles made of a protein called tau and plaques comprising small peptides called ABeta peptides generated from its precursor protein called APP. We have recently identified a new enzyme, Pin1 that regulates the structure and function of certain proteins such as tau and APP. Moreover, Pin1 is pivotal for protecting against tangle formation, ABeta accumulation and neurodegeneration. Notably, Pin1 is inhibited by various mechanisms in Alzheimer's patients. These results suggest that Pin1 deregulation is an important factor in Alzheimer's development, although its molecular targets and mechanisms are not fully elucidated. Our hypothesis in this proposal is that Pin1 might also regulate the function of presenilin 1, an essential component of the enzyme responsible for ABeta production, and that this regulation might be disrupted by some Alzheimer's mutations in presenilin 1. To test this hypothesis, we will determine whether Pin1 regulates presenilin 1 structure in a test tube, whether manipulating Pin1 function affects PS1 activity in cell culture and animal models, and whether this Pin1-dependent regulation is disrupted by presenilin 1 mutations. These studies would provide new insight into Alzheimer's development and might have important therapeutic implication.