Molecular mechanisms of gamma-secretase modulation central to Alzheimer’s disease

Alzheimer’s disease (AD), a progressive neurodegenerative disease and leading cause of dementia, exacts a tremendous toll on both the healthcare system and society broadly. Although the pathogenesis of AD is poorly understood, it centers on the production of so-called β-amyloid (Aβ) peptides, which are produced from amyloid precursor protein (APP) by the intramembrane protease γ-secretase. Indeed, mutations in the catalytic subunit of γ-secretase alter Aβ production profile and cause familial AD, making the protease a promising target for developing therapies to treat or prevent Alzheimer’s Disease. Specifically, developing agents that can modify γ- secretase activity to selectively reduce the formation of pathogenic β-amyloid species without affecting γ- secretase’s overall activity represent an attractive strategy to target AD. Despite significant progress in studying γ-secretase, we still do not understand how its catalytic activity and specificity are modulated at a mechanistic level. In the proposed project, we will apply a new approach and leverage novel reagents to investigate γ- secretase and its modulation. Using an interdisciplinary approach, we aim to elucidate how the cellular context and external factors modulate γ-secretase at the molecular level. We will also characterize new tools and reagents for γ-secretase and define their mechanism of actions. Collectively, the proposed studies will provide much needed insights into γ-secretase modulation and offer a molecular basis for Alzheimer’s disease pathogenesis and therapeutic development.