Uncovering Determinants of Neuronal Vulnerability in Alzheimer’s Disease

Neurofibrillary tangles (NFTs) and neurodegeneration occur only in very specific regions at early stages of Alzheimer’s disease (AD), while many regions remain virtually unaffected. Using the bacTRAP technology the lab developed to isolate mRNAs from specific neuron types, we molecularly profiled these very vulnerable neurons and other neurons that are much more resistant to pathological lesions of AD. We looked for genes enriched in vulnerable neurons compared with resistant neurons, and were able to pinpoint a list of these candidate vulnerability genes. Genetic analyses on these genes led by the laboratories of Drs. Tanzi and Stefansson uncovered one of these vulnerable neuron-enriched genes as genetically associated with AD in two very different populations. Dr. Tanzi further found three rare mutations in this gene that are present in individuals from three families with AD, indicating the importance of this gene in AD.

We now want to test whether these three mutations are indeed causative of the disease. For this we will test if the candidate gene is involved in the pathogenesis of the disease by analyzing mice invalidated for this gene. We also will study the three mutations, and investigate how they interfere with the protein function. Finally, we want to elucidate the pathways the candidate gene is involved in. We think this gene is potentially a crucial novel actor of AD pathogenesis that could explain specific vulnerability of certain neurons. Understanding its function and its molecular partners will yield new targets for the AD research community, for generating drugs that would prevent vulnerable neurons from degenerating.