Selective Cell Vulnerability in Alzheimer’s Disease

The goal of this project is to identify cells that are both most vulnerable and most resistant to Alzheimer’s disease in order to develop drugs that will protect the most vulnerable.

At the early stages of Alzheimer’s disease (AD), neurofibrillary tangles (NFT) and neurodegeneration occur only in very specific regions, while many regions remain virtually unaffected. Paul Greengard’s lab at the Rockefeller University recently developed a new procedure to compare the molecular profiles of very specific cell types inside the brain. They will apply this technology to mice in order to compare vulnerable regions with more resistant regions that don’t show any pathology until late stages of the disease. They will establish the molecular profiles of the different regions of interest, try to find genes that are common to all vulnerable regions or to all resistant regions and verify the region-specific expression of these genes in human brain tissue. Important differences between vulnerable and resistant cells might not be obvious at a normal physiological state,
but might become obvious only in a pathological environment. They will apply the bacTRAP technology (a platform to identify novel targets in specific cell types) to different AD mouse models, and study the molecular profile of the different regions in an AD-like environment. Then they will try to find genes that are modulated region-specifically in the context of AD and verify their findings in brain tissue of patients at different stages of AD.

These comparisons will yield lists of vulnerability genes that could potentially explain why vulnerable cells are vulnerable, or why resistance genes protect resistant cells from the pathology. By comparing these genes with AD susceptibility genes, they have the potential to identify genes that are crucial for AD pathogenesis. In future studies, they will modulate the expression level of the best candidates in neurons, and test the vulnerability of the cells thereafter. If these genes are indeed vulnerable or resistance genes, they could be very good drug targets aimed at protecting vulnerable cells.