TAUFUNALZ

Alzheimer Disease (AD) is the most frequent cause of dementia worldwide characterized by two main lesions the extracellular Ab1-42 plaques and the intracellular neurofibrillary tangles made of Tau proteins. Study of familial cases identified mutations in 3 genes, which led to the amyloid cascade hypothesis. However the disease remains to be better understood to develop efficient treatments. In the last 15 years, strong efforts allowed the identification of up to 76 AD-associated loci from sporadic cases. In order to translate these data into knowledge, we need to identify the functional genes within these loci and to understand how they mechanistically contribute to AD pathogenesis. For this purpose, thanks to Drosophila and mouse models, from the first 20 AD-associated loci, we successfully identified genes, like BIN1, unambiguously associated with the development of Tau pathology. These results led us to propose a genetically-driven synaptic failure hypothesis where Tau and the related GWAS-defined genes may be key elements of the dysfunction and loss of synapses in AD. Our project aims at further consolidating this hypothesis by identifying genes in the new 56 loci potentially functionally involved in Tau toxicity and in synaptic dysfunctions. It will be organized into 3 parts, (i) to identify AD genetic risk factors interacting with Tau toxicity through systematic screenings in drosophila model; (ii) to identify the synaptic function of the identified AD genetic risk factors with regards to Tau synaptic toxicity; (iii) to study the role of the identified AD genetic risk factors on Tau pathology in vivo in mice. Overall this project will identify new modulators of Tau pathology among the AD-associated genetic risk factors. It will dissect their interaction with Tau in physiological and pathophysiological contexts especially at the level of synapses. This will allow a better understanding of the disease and provide new candidates for therapeutic strategies.