Alzheimer's Disease Research - Completed Award
Paul Lombroso, M.D.
New Haven, CT
Title: The Role of STEP in Alzheimer's Disease
Non-Technical Title: New Targets for the Treatment of Alzheimer's Disease
Paul Greengard, Ph.D.
The Rockefeller University
Acknowledgements: Partial funding for this award was made possible through the generosity of the Kenneth and Ann Reim Trust Fund.
Duration: April 1, 2008 - March 31, 2011
Award Type: Standard
Award Amount: $400,000
By using transgenic animal models of Alzheimer's disease, this project seeks to test whether slowing down the activity of a particular molecular pathway can restore cognitive abilities.
Alzheimer's disease is a devastating disease with few effective treatments. Understanding the molecular basis of this disease should lead the way to new therapies. We are testing the hypothesis that a protein called STEP disrupts communication between neurons in Alzheimer's disease. STEP is a brain-specific protein that regulates the activity of several proteins required for the stabilization of memories. One of these proteins is the NMDA glutamate receptor. This receptor complex normally moves from intracellular pools to the neuronal surface where it can receive neurotransmitter signals required for the formation of long-term memories. The trafficking to and from membranes is a tightly regulated process, and STEP participates in this process. We recently discovered that STEP is inappropriately activated by beta amyloid. Moreover, active STEP removes NMDA receptors from neuronal surfaces. Inappropriate activation of STEP leads to loss of glutamate receptors and subsequent disruption to memory formation. We predict that reducing STEP activity will reduce the loss of NMDA receptors from their active sites. We will test this hypothesis by using an animal model of Alzheimer's disease with reduced levels of STEP proteins. We predict these mice will be 'rescued' and have restored cognitive abilities. These findings will have potential therapeutic implications.
Zhang Y, Kurup P, Xu J, Carty N, Fernandez SM, Nygaard HB, Pittenger C, Greengard P, Strittmatter SM, Nairn AC, Lombroso PJ. Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer's disease mouse model. Proc Natl Acad Sci U S A. 2010 Oct 18.
Kurup P, Zhang Y, Venkitaramani DV, Xu J, Lombroso PJ. The role of STEP in Alzheimer disease. Channels (Austin). 2010 Sep 6;4(5).
Kurup P, Zhang Y, Xu J, Venkitaramani DV, Haroutunian V, Greengard P, Nairn AC, Lombroso PJ. Abeta-mediated NMDA receptor endocytosis in Alzheimer's disease involves ubiquitination of the tyrosine phosphatase STEP61. J Neurosci. 2010 Apr 28;30(17):5948-57.
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.
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.