Dr. Karima Bettayeb: With Alzheimer’s disease, brain pathology is characterized by two hallmark findings: the presence of amyloid plaques resulting from the aggregation of the toxic protein beta amyloid (Aβ), and in later stages the presence of neurofibrillary tangles composed of the protein, tau. An important step in the process of Aβ formation is the cleavage of the amyloid precursor protein (APP) to release Aβ, a reaction catalyzed by the enzyme gamma-secretase (γ-secretase). Great efforts have been put into the development of γ-secretase inhibitors. But γ-secretase has crucial roles in the body in addition to making Aβ (more than 50 proteins have been identified as substrates). The inhibitors discovered so far also inhibit the maturation of substrates other than APP, some of which are crucial for various biological functions, and, when disturbed, lead to deleterious side effects such as cancer. Our laboratory discovered that Gleevec (imatinib), an FDA-approved drug, dramatically reduces Aβ levels and we have identified the target protein of Gleevec, which we named gamma-secretase activating protein (GSAP). Importantly, we found that the down-regulation of GSAP potently reduces Aβ in animal models without affecting other important substrates of γ-secretase. The therapeutic targeting of GSAP represents a unique alternative to circumvent the side effects associated with the overall inhibition of γ-secretase function. GSAP when discovered was a protein of unknown function. Since I started my post-doctoral work in the Greengard lab, my aim has been to better understand the function of GSAP and elucidate the mechanism by which GSAP selectively regulates γ-secretase cleavage to activate Aβ production. In order to characterize the biological activity of GSAP we searched for GSAP interacting proteins.
If you had to sum up your work in a few sentences, what would you say?
Dr. Karima Bettayeb: The inhibitors discovered so far against Alzheimer disease, reduce one of the two major hallmarks of AD (Aβ plaques but not tau tangles) by targeting an enzyme called γ-secretase. Unfortunately, these inhibitors have serious adverse side effects, due to a lack of specificity. My project was specifically designed to address this limitation. We discovered that Gleevec dramatically reduces Aβ levels via a protein that we named gamma-secretase activating protein (GSAP). Importantly, we found that the down-regulation of GSAP specifically reduces Aβ production in vivo. In order to characterize GSAP’s biological activity, we searched for GSAP-interacting proteins. I am currently looking for proteins that specifically control the activity of γ-secretase through GSAP modulation that could be used as novel therapeutic targets in order to circumvent the problems associated with non-selective γ secretase inhibition. These candidates are being validated through biochemical, molecular and behavioral experiments.
What results have you discovered thus far from your research, or what do you expect to find?
Dr. Karima Bettayeb: We identified the cellular partners of GSAP by several biochemical techniques. We identified interacting partners having potential relevance to the effect of GSAP on the production of Aβ peptide, based on their cellular functions. We performed functional validation of the candidates by measuring the effect of these proteins on Aβ production. Several of them have a dramatic effect on Aβ production. Several categories of proteins were found. We now propose to further validate and study these candidates and delineate the functional relationships that GSAP has with these interacting proteins using two major approaches: 1) addressing how these interactions affect APP processing in normal and pathological conditions, and 2) addressing how GSAP’s function is regulated by these candidates.
What impact might your work have on Alzheimer’s diagnosis or treatment in the future?
What directions can you see your work taking in the future?
Dr. Karima Bettayeb: Working on the GSAP interacting proteins will hopefully help us determine GSAP-dependent cellular pathway(s) and also identify possible regulators of GSAP. Besides GSAP itself we believe that enzymatic regulators of GSAP could also represent novel potential therapeutic targets. Gleevec, the only compound known to affect GSAP, is not appropriate for Central Nervous System (CNS) applications because it doesn’t accumulate in the brain. In this context, any novel small molecule compound compatible with CNS application and targeting GSAP function or its regulators (e.g., modulate APP maturation without affecting other γ-secretase substrates) might be useful for developing specific treatments for AD. We will screen for or develop new inhibitors of GSAP and GSAP activators that have the capacity to concentrate in the brain. This work could lead to the discovery of drugs that will prevent the aggregation of Aβ and plaque formation and, thus, the deterioration and death of brain cells responsible for the devastating symptoms of Alzheimer’s disease.
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