Strategy of translational research on Alzheimer's disease: targets, animal models and biomarkers

Alzheimer's disease causes severe cognitive alterations in humans and is associated with two main :pathologic processes: the beta-amyloid and tau pathologies. Imaging biomarkers can reveal the natural history of the disease and show an alteration of glucose metabolism and an evolving cerebral atrophy process. The discovery of new therapies against this disease relies on early stages of drug development that can be evaluated precisely only in animals. Our review focuses on transgenic mouse models of amyloidosis and on the mouse lemur primate model. Biomarkers in these animals may reveal endophenotypes that can be compared to human endophenotypes and help rationalizing decision-making during the development of new therapies. Animal models can also help to validate new hypotheses on disease mechanisms. We focus here on the protein misfolding hypothesis of Alzheimer as it will probably modulate our vision of the disease in forthcoming years. This hypothesis suggests that native A beta peptides become toxic when their conformation in alpha helices evolves into a beta-sheet conformation and also suggests that misfolded proteins can transmit their misfolded conformation to normal proteins.