Dynamics of the PS1 and PS2 γ-Secretase Complexes

The long term objective of the proposed studies is to gain a better understanding of the function of y-secretase and to develop specific y-secretase inhibitors for treatment of Alzheimer’s disease (AD). y-Secretase cleaves the amyloid precursor protein (APP) to generate the C-termini of Aβ peptides (Aβ40 and Aβ42), in the final step of amyloid production. Aβ, the major constituent of amyloid plaques found in AD, is believed to play a critical role in the neuropathogenesis of AD. It is known that Aβ42 is more prone to aggregation than Aβ40 and increased Aβ42 production may accelerate the pathological cascade leading to AD. Mutations in PS1 and PS2 that lead to familial early-onset AD (FAD) cause an increased ratio of Aβ42/Aβ40. The precise mechanism by which these mutations result in the increased ratio of Aβ42/Aβ42 is unknown. The hypothesis that the dynamics of the PS1- and PS2-associated y-secretase complexes regulate the production of Aβ40 and Aβ42 and that deregulation of this process leads to production of excessive Aβ42. Dr. Li will investigate the complex dynamics through integrated approaches incorporating biochemistry, cell biology and chemical biology. The proposed studies will help to uncover the regulation and function of y-secretase, thereby facilitating the development of selective inhibitors for AD therapy.