The Circadian Regulation of γ-secretase Activity in Alzheimer's Disease

Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disease which becomes increasingly prevalent worldwide with no effective treatments available causing a healthcare problem of epidemic proportion. Although the cause of AD is poorly understood, the disease progression is associated with β-amyloid peptide senile (Aβ) plaques and sleeping disorder, suggesting malfunction in internal biological clock and alteration of circadian rhythm. Interestingly, our initial data discovered that γ-secretase activity, the enzyme responsible for Aβ plaques generation, also exhibits a daily circadian oscillation. In this proposal we aim to reveal the molecular interaction between circadian function and γ-secretase activity and the connection to AD.

Alzheimer’s disease is devastating neurodegenerative condition causing severe cognitive and behavioral impairments and is associated with sleeping disorders, which suggests a malfunction in the internal biological clock. My project is focused on circadian rhythm, a mechanism that governs daily changes in our body such as sleep-wake cycle, body temperature and our hormone levels throughout the day. My goal is to understand, on a molecular level, the relationship between the circadian rhythm and the formation of senile plaques ­­­- toxic aggregates that form in the brain of Alzheimer’s patients, causing memory loss and cognitive decline. In my research, I have discovered that the activity of the specific enzyme that forms these harmful plaques is influenced by the circadian rhythm. I now aim to characterize the activity of the enzyme at different times of the day and see how it changes with the progression of disease and age. My second aim is to understand how this enzyme behaves when the biological clock is disrupted. And finally, my goal is to decipher the specifics of the molecular mechanism by which circadian rhythm regulates the fluctuation of the enzyme’s activity. I hope that when my study is complete, the research will lead to the development of an innovative treatment- administrated according to a schedule that corresponds to the rhythmic activity of the plaque formation enzyme. Specifically, we could administer an inhibitor of the enzyme at specific times of the day, to maximize the effectiveness of the treatment and minimize adverse effects.