Aims

The amyloid cascade is central for the neurodegeneration disease pathology, including Alzheimer’s and Parkinson’s diseases, and remains the focus of much current research. Increasing evidence has accumulated demonstrating critical role of pro-inflammatory S100A9 in the amyloid-neuroinflammatory cascade in these diseases.

Methods

AFM, fluorescence, immunohistochemistry, western blots, ELISA, circular dichroism

Results

We demonstrated that S1009 protein is amyloidogenic and form amyloids both in vitro and in vivo in cell models and in neurodegenerative diseases. In Alzheimer’s, deciphering the interaction between proinflammatory S100A9 protein and Aβ peptide and their co-aggregation mechanisms are particularly important since these lead to amyloid plaques formation and neural cytotoxicity By using the combination of mass and charge distributions of amyloids together with reconstruction of the differences between them and detailed microscopy reveals that co-aggregation involves templating of S100A9 fibrils on the surface of Abeta42 amyloids. Kinetic analysis further corroborates that the surfaces available for the Abeta42 secondary nucleation are diminished due to the coating by S100A9 amyloids, while the binding of S100A9 to Abeta42 fibrils is validated by a microfluidic assay. We demonstrate that synergy between charge detection mass spectroscopy, microscopy, kinetic and microfluidic analyses opens new directions in interdisciplinary research.

Interactions of S100A9 with small molecules as potential regulators of its amyloid aggregation and functions, including interactions with NCAM1 peptide constructs, oleuropein aglycone, polyoxometalates and DOPA-derivatives, are discussed in the light of their potential therapeutic applications.

Conclusions

S100A9-driven amyloid-neuroinflammatory cascade could be a common denominator in a range of neurodegenerative diseases and therefore the common target for theraputic interventions.