Regulation of Alzheimer’s Disease Aß Production by Lipid Modification of y-secretase
2006 Seed Grant
Gopal Thinakaran, Ph.D.
The University of Chicago

Alzheimer’s disease is a devastating disorder for which there is no cure available at present. It is clear from previous studies that production and deposition of beta-amyloid peptides is causally linked to Alzheimer’s disease. Understanding the molecular mechanisms involved in the production of betaamyloid peptide is central to Alzheimer’s disease research. Several Alzheimer’s disease therapeutics being developed aim at reducing beta-amyloid production or deposition in brain, including beta-amyloid vaccination and pharmacological inhibition of y-secretase. Although vaccination studies in transgenic mouse models were extremely promising, human vaccination trials have met with unfortunate consequences of brain inflammation, including death of one patient. On the other hand, studies in animal models showed that inhibition of y-secretase using highly selective inhibitors still led to adverse effects related to inhibition of y-secretase processing of Notch, such as gross enlargement of spleen, skin inflammation, abnormalities in hematopoiesis etc.

Dr. Thinakaran and his lab believe that their studies will provide proof of principle for a novel strategy to reduce beta-amyloid production in the brain without adversely affecting Notch processing. Their preliminary studies in cultured cells strongly support this hypothesis, and they plan to use funding from their BRF seed grant to extend their studies in transgenic mice, as a logical step towards establishing lipid modification of y-secretase as a potential target to combat Alzheimer’s disease betaamyloid production and deposition.

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