August 16, 2010
Current Fisher Center Alzheimer’s Research Projects
Paul Greengard, Principal Investigator
1. Gamma secretase activating protein and its binding proteins
Gamma secretase is the critical enzyme that is responsible for the formation of beta amyloid. Gamma secretase is composed of several different proteins, among which is presenilin. We recently discovered a new protein that controls, or regulates gamma secretase, thus, telling it how much beta amyloid to make. We want to discover new drugs that prevent or slow down the rate at which gamma secretase makes beta amyloid because such drugs would prevent or stop the progression of Alzheimer’s. We feel that we can accomplish this by designing drugs that target our activator protein.
Most current g-secretase inhibitors lack discrimination between g-cleavage of APP and other substrates including Notch, and therefore show unacceptable toxicity after chronic administration to animals. Recent studies from our laboratory demonstrate that g-secretase mediated production of Ab can be inhibited by the drug, Gleevec without affecting Notch cleavage. We now have discovered the Gleevec binding protein responsible for these effects and named this uncharacterized protein gSAP for gamma-secretase activating protein.
2. Characterization of a novel cell surface protein
Beta amyloid is harmful to brain cells when it is produced in too great of a quantity. We recently discovered a protein on the surface of brain cells that mediates the damaging effects of beta amyloid. If we are successful in making drugs that control that protein, we will have found a way to limit the damage caused by beta amyloid and, thus, control or stop the course of the disease.
Alzheimer’s disease (AD) is a neurodegenerative disease manifested by memory impairments and severe dementia. A pathological hallmark of AD is progressive deposition of insoluble senile plaques containing the amyloid-peptide (Aβ). Aβ peptide is highly hydrophobic and exists in different aggregation states, ranging from monomers to small oligomers to fibrils to amyloid plaques. Recent studies indicate that prefibrillar, soluble Aβ oligomers are not only the building blocks of fibrillar plaques, they themselves are also neurotoxic.
3. Comparison of vulnerable and resistant cells in Alzheimer’s disease
The goal of this project is to discover why only certain parts of the brain are susceptible to the ravages of Alzheimer’s and why other parts of the brain seem to be resistant. The answer is being sought by analyzing the activities of large numbers of genes that are expressed in different types of brain cells. The answers are likely to teach us how to protect sensitive brain regions against the ravages of Alzheimer’s.
Only some aspects of cognition are affected during the early steps of Alzheimer’s disease. The inability to form new memories is the very first manifestation of the ongoing pathology. The specificity of the clinical symptoms has its molecular counterpart. Amyloid plaques and neurofibrillary tangles, the two molecular hallmarks of the disease do not form uniformly throughout the brain. They accumulate in very specific regions of the brain during early phases of the disease, namely the regions involved in the formation of new memories: the entorhinal cortex and the hippocampus. On the contrary, some other regions are not affected by the pathology even at very advanced stages. We would like to understand the basis for the vulnerability of some brain regions to Alzheimer’s disease pathology.