The Role of STEP in Alzheimer's Disease
STriatal Enriched tyrosine Phosphatase (STEP) is a protein that removes a phosphate group from glutamate receptor proteins (called NMDA) found on the surface of nerve cells, promoting their internalization. Drs. Paul Lombroso, Paul Greengard, and colleagues generated mice lacking STEP to understand this protein's role in nerve cell communication breakdown and Alzheimer's disease. These researchers found that reducing STEP activity reduced the internalization of NMDA receptors from their active sites on nerve cells. This retention of NMDA receptors appeared to rescue the cognitive deficits in Alzheimer's disease mice. These exciting findings suggest new options for therapeutic interventions. As a result of the discoveries from this research grant, Drs. Lombroso and Greengard will design small molecule inhibitor drugs to decrease STEP activity and begin to test them in animal models of Alzheimer's disease. Already, they have initiated a search for drug candidates in collaboration with the Laboratory for Drug Discovery at Harvard.
Zhang Y, Kurup P, Xu J, Carty N, Fernandez SM, Nygaard HB, Pittenger C, Greengard P, Strittmatter SM, Nairn AC, Lombroso PJ. (2010). Genetic reduction of STEP tyrosine phosphatase reverses cognitive and cellular deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):19014-9. Epub 2010 Oct 18.
Baum ML, Kurup P, Xu J, Lombroso PJ. (2010). A STEP forward in neural function and degeneration. Commun Integr Biol. 2010 Sep;3(5):419-22.
Kurup P, Zhang Y, Venkitaramani DV, Xu J, Lombroso PJ. The role of STEP in Alzheimer's disease. Channels (Austin). 2010 Sep-Oct;4(5):347-50. Epub 2010 Sep 6.
First published on: June 10, 2008
Last modified on: June 16, 2011