Probing of the role of neuronal activity in amyloid aggregation in Alzheimer’s disease using novel biophysical tools

Structural analysis of amyloid protein aggregation is central to Alzheimer’s disease (AD), however, it is incredibly challenging to elucidate neurotoxicity in structurally transient amyloid aggregates due to the lack of sensitive methods allowing structural analysis in situ.I propose an interdisciplinary study of the molecular structures of amyloid aggregates directly in individual cells.

Using this novel approach (that will be developed herein), combined with high-resolution synchrotron-based spectromicroscopy (MAX IV), my research group will address the role of neuronal activity and the sub-cellular environment in the formation of neurotoxic amyloid structures on individual neurons.The project will (1) lead to a new multi-dimensional interdisciplinary research strategy to investigate protein structures directly in neurons; (2) provide new knowledge on early changes in amyloid protein structures triggering neuronal death using the combination of cutting-edge nanotechnologies.The proposed research program will have multiple-fold impacts, on the one hand making significant advances to address the fundamental question of AD (neuronal activity- amyloid structure-neurotoxicity), and on the other, by developing the methodological framework to critical scientific questions that need to be explored in other amyloidopathies such as Parkinson’s, Lateral amyloidosis, diabetes type II,  etc.

Timeline: 1) approach development: years 1-2; 2) structure-neurotoxicity study: years 2-5.