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Alzheimer's Disease Research
Completed Award

Photo Pending

Yueming Li, Ph.D.

Sloan-Kettering Institute for Cancer Research
New York, NY

Title: Effects of aging and gender on gamma-secretase
Non-Technical Title: Aging and gamma-secretase

Duration: April 1, 2010 - June 30, 2013
Award Type: Standard
Award Amount: $400,000

Summary:

The vast majority of Alzheimer's disease (AD) is sporadic in nature and has no known genetic basis. Aging and gender are common risk factors for the development of AD. This project will elucidate the role of aging and gender in the modulation of gamma-secretase that is linked with AD.

Details:

The long term objective of the study is to investigate the effect of aging and gender on the function of gamma-secretase, a complex of proteins involved in the generation of toxic amyloid beta. Aberrant gamma-secretase activity is associated with Alzheimer's disease (AD). The vast majority of AD is sporadic in nature and has no known genetic basis. Aging and gender are common risk factors for the development of AD. How aging and gender affect gamma-secretase is poorly understood. The objective of the study is to uncover the mechanism of aging and gender in the regulation of gamma-secretase activity and specificity. Therefore, we will investigate the relationship between aging and gamma-secretase. The first aim will examine the effect of aging and gender on the dynamics of gamma-secretase complexes using an integrated approach of enzymology and chemical biology. The second aim will determine the effect of aging and gender on changes of the active site within the gamma-secretase complex using a multiple photo-affinity probe" approach. The proposed studies will provide insights into the role of altered gamma-secretase activity during aging and in the development of sporadic AD and in neurodegeneration. These studies will provide a foundation for investigating the mechanism of human aging and gender in the most common forms of AD and facilitate the development of effective AD therapies."

Publications:

Chau DM, Crump CJ, Villa JC, Scheinberg DA, Li YM. Familial Alzheimer Disease Presenilin-1 Mutations Alter the Active Site Conformation of γ-secretase. J Biol Chem. 2012 May 18;287(21):17288-96. Epub 2012 Mar 29. PubMed Icon Google Scholar Icon

Crump CJ, Am Ende CW, Eric Ballard T, Pozdnyakov N, Pettersson M, Chau DM, Bales KR, Li YM. Development of clickable active site-directed photoaffinity probes for gamma-secretaseJohnson DS. Bioorg Med Chem Lett. 2012;22(8):2997-3000 (Co-corresponding authors). PubMed Icon Google Scholar Icon

Ahn K, Shelton CC, Tian Y, Zhang X, Gilchrist ML, Sisodia SS, Li YM. Activation and intrinsic {gamma}-secretase activity of presenilin Proc Natl Acad Sci U S A. 2010 Nov 29. [Epub ahead of print] PubMed Icon Google Scholar Icon

Progress Updates:

More than 90% of all Alzheimer's disease (AD) cases happen spontantously and are of unknown origin (often called sporadic). Aging and gender are common risk factors for the development of AD. The study of rare forms of autosomal-dominant early onset Familial Alzheimer’s Disease (FAD) helps to discover the underlying molecular mechanisms of AD. FAD mutations have been linked to three genes: APP, presenilin 1 (PS1) and presenilin 2 (PS2). Growing evidence suggests that these FAD mutations affect gamma-secretase and the production of toxic beta-amyloid peptides. Dr. Yueming Li’s team will investigate whether risk factors and genetic mutations exhibit a similar effect on gamma-secretase protein.

How aging and gender influence the structure and function of the gamma-secretase protein has been elusive due to its characteristics of embedding in cell membranes, its chemistry, and a lack of high resolution structure of the bundle of proteins that associate with the gamma-secretase complex. Dr. Li’s team has developed a method called "photophore walking" to investigate how the shape of the active site of gamma-secretase is changed by aging and gender. They first validated this practical approach by investigating the effect of PS1 protein mutations on the structure and function of gamma-secretase in mice with early-onset Alzheimer’s disease. They have shown that both aging (from 4- to 32-month old mice) and gender have an effect on gamma-secretase activity and specificity, which is reminiscent of FAD gene mutations. These studies provide a model system for the study of the effect of aging and gender on the structure and function of gamma-secretase and offer a molecular basis of sporadic AD pathogenesis as well as facilitate the development of effective AD therapies.

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