Speaker: Dr. Jean-Pierre Roussarie, Rockefeller University, NY
Host: Adrien Peyrache
At early stages of Alzheimer’s Disease (AD), neurofibrillary tangles (NFT) and neurodegeneration occur only in very specific brain regions and types of neurons, while many regions remain virtually unaffected. We set out to understand why vulnerable neurons, namely neurons from layer II of the entorhinal cortex (ECII) and pyramidal cells from CA1 form NFT and degenerate so readily. For doing so, we profiled projection neurons from seven different brain regions in the mouse using the bacTRAP technology, some vulnerable and some more resistant to AD. In collaboration with Olga Troyanskaya (Princeton University), and using publicly available data for protein-protein interaction and gene-gene interaction, we constructed functional networks for each of these seven types of neurons. Leveraging these functional networks together with genome-wide association study results, we « reprioritized » genes based on how functionally related they are to the AD pathology, within the molecular context of each cell type. We were able to show that the reprioritized genes are regulated by age and by the presence of amyloid plaques in neurons from ECII. We show which pathways, enriched among the top-reprioritized genes, contribute to NFT formation, and which pathways, enriched in ECII, might make these neurons particularly vulnerable to the AD pathology. We think we highlight for the first time a set of genes that might be the missing link between Amyloid plaques and NFT.