Comparing in vitro protein aggregation modelling using strategies relevant to neuropathologies

Although protein aggregation is involved in physiological ageing-related processes, it is also remarkably associated with several neuropathologies, including Alzheimer´s (AD) and Parkinson´s disease (PD). The first is characterized by hyperphosphorylated tau protein and Aβ peptide deposition, thus forming intracellular neurofibrillary tangles and extracellular senile plaques, respectively; while, in PD, α-synuclein aggregates and deposits as Lewy bodies. Considerable research has focused on developing protein aggregation models to be explored as research tools. In the present work, four alternative models for studying protein aggregation were explored and compared, namely treatment with: the toxic Aβ peptide, the isoflavone rotenone, the ATP synthase inhibitor oligomycin, and the proteosome inhibitor MG-132. All treatments result in aggregation-relevant events in a human neuronal cell line, but significant model-dependent differences were observed. In terms of promoting aggregate formation, Aβ and MG-132 provoked the greatest effect, but only MG-132 was associated with an increase in the HSP-70 chaperone. In fact, the type of aggregates formed appear to be dependent on the treatment employed, and supports the hypothesis that Aβ exposure is a relevant AD model, and rotenone is in fact a good model for PD. Furthermore, the results revealed that protein phosphorylation is relevant to aggregate formation and as expected, tau co-localized to the deposits formed in the Aβ peptide aggregate induction cell model. In summary, different molecular processes can be induced by using distinct aggregation modelling strategies, and these can be used to study different protein-aggregation related processes associated with distinct neuropathologies.