Alzheimer's Disease Research - Current Award

	Paul Lombroso, M.D. Yale University New Haven, CT Title: The Role of STEP in Alzheimer's Disease Non-Technical Title: New Targets for the Treatment of Alzheimer's Disease 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
Summary: 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.

Details:

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.

Progress Updates:

Alzheimer’s disease (AD) is a devastating disorder, with few effective treatments. Understanding the proteins, chemicals and pathways involved in the development of this disease should lead the way to therapies. We are testing the hypothesis that a protein called STEP is one culprit that disrupts communication between neurons in AD. STEP is a brain-specific protein that regulates the activity of several proteins required for the stabilization of memories. One of these memory-stabilizing proteins is the NMDA glutamate receptor. This receptor normally moves from protein pools within neurons to the surface of the nerve cell, 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, in which STEP is a participant. We recently discovered that STEP levels are increased in the cortex of human Alzheimer’s brains as well as in the cortex of mouse models of AD. The increase in STEP levels is caused by the toxic peptide beta-amyloid that prevents the normal degradation of STEP in cells. The increase in STEP levels removes NMDA receptors from the nerve cell surfaces, taking them to places within the cell where they can’t be involved with memory stabilization. Inappropriate activation of STEP leads to loss of glutamate receptors (other important memory proteins) and subsequent disruption of memory formation.

We predicted that reducing STEP levels would reduce the loss of NMDA receptors from their active sites, and, after interpreting results from research completed within the last year, we are finding that we are rescuing the cognitive deficits in mouse models of AD. These findings have potential therapeutic implications, as we hope to find small molecule drug inhibitors that decrease STEP activity. We have initiated a drug discovery program in collaboration with the Laboratory for Drug Discovery at Harvard University, and are testing lead compounds in our Alzheimer’s disease mice in an effort to reverse cognitive deficits in these mice.