The molecular events leading to Alzheimer’s disease (AD) are largely unknown, in spite of this being one of the most examined questions in modern biomolecular research. This means that new angles are needed. Here we propose one new approach rooted in a physicochemical and molecular framework considering protein solubility, solubilization and modification, as well as protein-lipid interactions, which we place in context together with molecular neurochemistry insights on in vivo aggregation dynamics, plaque maturation and synaptic changes upon disease progress.
The goal is to answer the following scientific questions:
1) Is decreased solubility of amyloid β (Aβ) peptide a cause or a consequence of AD?
2) Is the gain of Aβ toxicity in AD caused by changes in the composition and molecular environment of structurally distinct amyloid plaques?
3) How does the structural conformation of Aβ aggregates relate to Aβ toxicity?
These questions are addressed through a concertated research effort involving advanced in vitro and in situ experiments using state of the technologies, including imaging mass spectrometry and solid-state NMR.
We combine top-down and bottom-up approaches to study molecular mechanisms behind amyloid composition, deposition and toxicity, which processes are a cause or consequence of the pathophysiological changes during AD onset and progression. This requires studies of relevant biological samples with complex composition as well as model systems with well-defined compositions.
