SINGLEMOLALZHEIMER · Dissecting Alzheimer’s disease at a single molecule level
FP7 — People (Marie Curie Actions)
- Duration
- 2011-01-01 → 2013-12-31
- EU contribution
- €164,459
- Participants
- 1
- Scheme
- MC-IEF
Lines connect the coordinator with its partners.
Results in brief
Dissecting Alzheimer’s disease at a single molecule level
This project has been the first one to systematically apply single molecule tracking techniques to investigate the molecular basis of Alzheirmer’s disease. This approach has allowed to discover new features normally not accessible with standard methods based on data averaging. This study has contributed to add new information on the biology of the toxic Abeta petide oligomers by describing their dynamic behaviour on the plasma membrane of living cells. Additional results on the interaction of Abeta oligomers with components of the plasma membrane have also provided proof of evidence for a mechanism of toxicity that was object of debate in the past. Although the interaction of Abeta oligomers with the cellular membrane is a well-known process, the manner through which they cause cell dysfunction can depend on several factors. The findings related to this project have revealed a new potential mechanism of toxicity attributable to the loss of function of specific membrane components consequent to an alteration of their mobility caused by the binding to slowly diffusing Abeta oligomers. The dynamic behaviour and the membrane effects of toxic amyloid aggregates formed by proteins or peptides other than Abeta have also been object of investigation. Results similar to those obtained in the case of Abeta oligomers were found for amylin (involved in the development of type II diabetes) and prion sup35, supporting the hypothesis that amyloid diseases share similar mechanisms of toxicity.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- LABORATORIO EUROPEO DI SPETTROSCOPIE NON LINEARI · Sesto-Fiorentino (Fi)CoordinatorItaly
Links
Data: CORDIS, © European Union