Grant: Team Grant: Alzheimer's Disease France-Quebec

The amyloid cascade hypothesis in AD has fulfilled its aim in fostering research but appears to be now insufficient to explain the mechanisms of the disease. The role of molecules interacting with Abeta peptide appears essential. Associated proteins have been thoroughly investigated. However, technical difficulties makes the study of lipids much more difficult. Cholesterol is an abundant component of the senile plaque, modulates A¿ secretion, and is transported by ApoE whose E4 allele is the most significant risk factor of AD. This large scale project will bring together researchers from France, Canada and Quebec who have been successfully working in this field for many years and have complementary areas of expertise (genetics, neuropathology, mass spectrometry, molecular and cellular biology, animal models, gene therapy). The project also involves experts who have developed new technological tools such as MALDI and SIMS imaging of human tissue. These new tools will increase the chance of making discoveries in poorly explored territories of AD research. We will improve our knowledge on the role of cholesterol in the formation of amyloid deposits through an exhaustive investigation on human tissues, in vivo transgenic models and in vitro transfected cells, exploring transport and efflux of A¿ and cholesterol, modulation of APP processing by cholesterol (and cholesterol derivatives) and finally gene therapy. The project will have practical implication on finding 1) new genetic risk factor for AD 2) new biomarkers (enlarged endosome) and 3) new therapeutic approaches that could be translated into clinics. Moreover, the project will also bring results in the development of new microscpy capacities (mass spectrometry imaging) that could deeply modify the way human and animal material are investigated.