A.G. Bobylev, L.G. Marsagishvili, M.D. Shpagina, Z.A. Podlubnaya

Amyloids diseases, including neurodegenerative diseases (e.g., Alzheimer-s and Parkinson-s), nonneuropathic systemic diseases (e.g., AL amyloidoses), nonneuropathic localized diseases (e.g., type II diabetes), and prion encephalopathies are generally thought to be caused by amyloidogenic protein/peptide misfolding and aggregation. At least 34 different proteins/peptides have been identified to date that can fold abnormally, form highly stable insoluble fibrils (amyloids) and are associated with pathology. However, the mechanism by which these proteins/peptides gain their neurotoxic function upon misfolding and aggregation remain unclear. Amyloids are deposited in different organs and tissues and arise as a result of inherited or acquired abnormality of protein folding. The availability of beta-sheet structure is necessary for amyloid formation. As a rule, protein molecules first undergo partial unfolding, accompanied by an increase in beta-sheet content, then associate with each other to form oligomers, and finally assemble into fibrils. Senile plaques composed mainly by beta-amyloid are one of the pathological hallmarks of Alzheimer-s disease (AD). Creating early diagnostics and the search of drugs for therapy of amyloidoses are actual tasks. Trying to decrease the production of Abeta amyloids is also envisaged as a promising approach to prevent neurodegeneration in AD. We have recently discovered new amyloid muscle proteins of titin family (X-, C-, H-proteins) offering some advantages for solution of the above tasks. Molecules of these proteins already contain 90% of beta-sheet structure and unlike other proteins, form easily amyloids under mild conditions. Sufficient quantities of these proteins in muscles also promote the intensification of investigations in such systems. Moreover, we showed their capacity to form amyloid fibrils similar to those formed by Abeta-peptides in vitro and found in the AD brain. Earlier we demonstrated also that tetracycline and fullerene C60 disrupted amyloids of the pro-teins and those of Abeta peptides, like the effect of tetracycline on amyloids formed by tau and prion pro-teins, by amylin and hintingtin. This denotes the possibility of similar approaches to the disruption of different amyloids due to the similarity of their physicochemical properties. Tetracycline and fullerenes not only disrupted mature amyloid fibrils but prevented the formation of new amyloids. Such a double effect of drugs is very important in therapy of amyloidoses. It is known that amyloid aggregates of different proteins and peptides are cytotoxic, inducing cell death. Study on the cytotoxicity of amyloids in cell cultures and its decrease in the presence of different preparations help to appreciate their antiamyloidogenic properties. Our results suggest that along with the electron microscopy, the registration of amyloid cytotoxicity in vitro in the absence and in the presence of drugs can be additional promising approach to the search for the most effective candidates for preventing and treating amyloidoses. Further testing of anti-amyloidogenic properties of fullerene C60 and its modified nano-compounds in amyloid protein systems of titin family will favor the creation of new nanotechnology in therapy of amyloidoses.