SINGLEMOLALZHEIMER · Dissecting Alzheimer’s disease at a single molecule level

Fibrillar deposits of proteins are the hallmark of amyloid diseases, amongst which Alzheimer’s disease stands out as the most widespread neurodegenerative pathology of the brain. Neuronal dysfunction is currently attributed to the interaction of A-beta oligomers with the plasma membrane. Several scenarios have been proposed, but the mechanisms of binding of the oligomers to the cell membrane and their subsequent toxicity is still unclear. The dependence of the proteolytic production of A-beta peptide on the distribution of the amyloid precursor protein (APP) and its proteases on the plasma membrane is also matter of debate.The discrepancies arising from the models proposed may be due to the fact that most of the current research on the molecular mechanisms of Alzheimer’s disease is based on averaged results obtained using bulk methods. In this case, many essential details can be missed. The goal of this project is to provide a better understanding of the pathogenesis of Alzheirmer’s disease by studying the dynamic features of this complex system at a single molecule level. In particular, the immediate aim will be to apply single molecule tracking techniques to characterize the mobility of A-beta oligomers on the plasmamembrane of living neuronal cells, especially with respect to synaptic structures and membrane rafts. In addition, I will study the surface mobility of the transmembrane proteins involved in A-beta production, namely APP, alpha-, beta-, and gamma-secretase. In the light of the influence of cholesterol on A-beta generation, my aim will be to study the dynamic response of these proteins to changes in cell cholesterol levels, and their location inside or outside lipid rafts. Overall, this project represents an innovative approach to understand the basic mechanisms underlying the development of Alzheirmer’s disease and to suggest new strategies for the cure of this pathological condition.