Insight of the Cytotoxicity of the Aggregates of Peptides or Aberrant Proteins: A Meta-Analysis

Aberrant proteins or peptide aggregates form soluble oligomers or nanofibrils that can cause a wide range of amyloidosis diseases, including Alzheimer's disease (AD). The mechanisms of their cytotoxicity, however, remain controversial and poorly understood, greatly hindering the development of AD drugs. Here we report a comprehensive evaluation of the cytotoxicity of the aggregates by meta-analysis. The analysis indicates that the cytotoxicity of the aggregates converges in a narrower range in the mass concentrations than in the molar concentrations, suggesting that it is the weight of the aggregates rather than the number of the molecules that dictates the cytotoxicity. This new perspective implies that these aggregates are likely to have non-specific interactions with cells to cause cell death. The comparison of several existing theories regarding cellular volumes supports that the aggregates may result in crowding effect and increase the free energy, thus resulting in instability of the cells.