Understanding the Origins of Age-Dependent Neurodegeneration: Cross-Talk Between the Amyloid and Neuroinflammatory Cascades Studied by Advanced Biophysical Methods.

Age-dependent neurodegeneration, including Alzheimer’s (AD) and Parkinson’s (PD) diseases, represents one of the greatest and most rapidly developing challenges to human health and welfare in modern world.

No causative therapies are available, related to a serious lack of understanding of complex biomolecule interactions implicated in disease, including hetero-amyloid aggregation, how this affects cell homeostasis and how it can be targeted.

We discovered the critical role of S100A9-driven amyloid-neuroinflammatory cascade in AD, PD and traumatic brain injury as AD precursor state.

Now we propose an integrated study of the molecular, cellular and tissue mechanisms of this cascade and how it modulates disease pathology.

The mechanisms of hetero-assembly of proinflammatory S100A9/A8 into amyloid complexes with Aβ in AD, α-synuclein in PD and other proteins, if understood, provide insights into a key denominator of the origin of neurodegeneration (amyloid formation, inflammation and tissue damage). The S100A9 driven self-assembly will be primarily targeted by therapeutic lead compounds to inhibit/reverse it.

The diagnostic potential of S100A9 interactome will be explored.

Breakthrough will be achieved by using large array of advanced biophysical methods from in vitro to ex vivo studies, in which we have expertise, as AFM, force tissue mapping, AFM-IR, charged-detection mass-spectrometry, FTIR, NMR, Biacore, confocal microscopy, cryoelectron microscopy and others.