The Relationship between Biological Clock and γ-secretase, the Enzyme Responsible for Generating Senile Plaques in Alzheimer’s Disease

Eitan Wong, PhD
Memorial Sloan-Kettering Cancer Center (New York, NY)


Yueming Li, PhD
Year Awarded:
Grant Duration:
July 1, 2019 to June 30, 2021
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Postdoctoral Fellowship
Award Region:
US Northeastern

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.

About the Researcher

Dr. Eitan Wong received his PhD in 2014 from the Weizmann Institute of Science, Israel. Under the supervision of Dr. Irit Sagi of the Biological Regulation Department, Dr. Wong focused on Metalloprotease regulation and inhibition, acquiring extensive experience and understanding of the regulation of the protease network. In 2015, Dr. Wong joined the laboratory of Dr. Yueming Li at The Pharmacology and Chemical Biology department of the Memorial Sloan Kettering Cancer Center (MSKCC), New York. As a post-doctoral fellow at MSKCC, Dr. Wong. is conducting research to understand the molecular mechanism of Alzheimer’s disease, emphasizing the role of proteolytic activity. At MSKCC, Dr. Wong is exposed to world-class leaders in neuroscience and neurodegeneration, learning the cutting-edge scientific methodology and current ideas. Due to a fruitful collaboration with the late Dr. Paul Greengard (Rockefeller University) a Nobel Laureate and a pioneer in the field of Alzheimer’s and neurodegenerative disease, Dr. Wong was able to prove the existence of specific protease modulator that can directly influence Aβ plaque formation in Alzheimer’s disease. In addition, during Dr. Wong’s work at MSKCC, he discovered that γ-secretase activity appears to fluctuate depending on time of the day, suggesting a circadian rhythm regulation. As a biochemist with extensive experience in molecular and cellular protease regulation, Dr. Wong is well positioned to decipher the underlying mechanism of circadian regulation of protease activity and it effect on the pathogenesis of Alzheimer’s disease.

Personal Story

Alzheimer’s disease is becoming increasingly prevalent with no effective cure in sight, causing a healthcare problem of epidemic proportions and suffering to millions of individuals and their families. Yet even after decades of extensive research, the underlying causes of Alzheimer’s disease remains unknown. The pressing need to decipher the molecular mechanism of the disease so that we could develop an effective treatment is what drew me to this field. I believe my research could shed light into biological clock involvement in Alzheimer’s disease pathogenesis and ultimately developing an innovative approach of treatment. Namely, by understanding the contribution of circadian rhythm to disease progression we can offer a path to a time dependent treatment to better align with the biological clock of patients. Currently, similar approaches are used in different disease treatments, and I hope my research could lay the ground for Alzheimer’s disease treatment as well. I want to express my deepest appreciation to the BrightFocus foundation for recognizing the potential of this exciting research and giving me the opportunity to explore this path.

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