Molecular Biophysics and Soft Matter
 
   

 


Amyloid formation and Cytotoxicity


Primary sources and mechanisms of the amyloid-induced cellular toxicity are topics of a large debate, in particular addressing the question of whether prefibrillar oligomers and rather than fibrils are the prime toxic agents. A number of studies indicate that fibrils are harmless to the cells and they may represent an escape route for smaller, more toxic aggregates. Conversely , there are also experimental evidences demonstrating the neurotoxicity and cytotoxicity of amyloid fibrils formed from different proteins. The structural definition of the cytotoxic species is complicated by the polymorphism of amyloid fibrils arising by multiple aggregation pathways promoted in different conditions such as aggregated species rising from the same protein but characterized by distinct morphologies (e.g. twisted or parallel assemblies of protofibrils) exhibiting significantly different behaviours in cell cultures. Moreover, it is important to focus the attention on the recently suggested idea that not only a single uniform species but rather a continuum of cross-β-sheet containing aggregates induce cell death this may shed new light on the evidences indicating that the behavior of cells in culture treated with destabilised non-pathogenic proteins show analogies with cells in pathologic conditions.

This indication, together with the observation that the oligomers and fibrils are characterized by common structural features suggests that common mechanisms for cytotoxicity could exist and have to be perused in common interactions involved in aggregation. Those cytotoxic properties are likely to arise from the exposure of internal regions due to conformational changes occurring during aggregation. The detailed comprehension of the cytotoxicity mechanisms and of the role of intermediate species can only be achieved by kinetic observation of aggregation processes simultaneously with the observation of their effect on cells. In this context, studies on model proteins in different conditions are required to explore the generality of these observations.

 

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