Alzheimer’s

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.

Other Grants

Lindsay M. De Biase, Ph.D., University of California Los Angeles
The Role of Microglial Lysosomes in Selective Neuronal Vulnerability
Synapses, the sites of signaling between neurons in the brain, play essential roles in learning, memory, and the health of neurons themselves. An enduring mystery is why some neurons are…
How the Nervous System Constructs Internal Models of the External World
As animals navigate their environments, they construct internal models of the external sensory world and use these models to guide their behavior. This ability to incorporate ongoing sensory stimuli into…
Xiaojing Gao, Ph.D., Stanford University
When Neural Circuits Meet Molecular Circuits: Quantitative Genetic Manipulation with Single-cell Consistency
Cells are the building blocks of our bodies. We get sick when the cells “misbehave”. The way modern gene therapies work is to introduce genes, fragments of DNA molecules that…
Rafiq Huda, Ph.D., Rutgers University
Conducting the Orchestra of Movement—Functional Role of Striatal Astrocytes in Health and Disease
Movement requires coordinated activity across a large brain-wide network. The striatum is a particularly important part of this circuit; it integrates motor-related information from many distinct brain regions to regulate…