Abstract
The prevailing opinion is that prefibrillar β-amyloid (Aβ) species, rather than end-stage amyloid fibrils, cause neuronal dysfunction in Alzheimer’s disease, although the mechanisms behind Aβ neurotoxicity remain to be elucidated. Luminescent conjugated oligothiophenes (LCOs) exhibit spectral properties upon binding to amyloid proteins and have previously been reported to change the toxicity of Aβ1–42 and prion protein. In a previous study, we showed that an LCO, pentamer formyl thiophene acetic acid (p-FTAA), changed the toxicity of Aβ1–42. Here we investigated whether an LCO, heptamer formyl thiophene acetic acid (h-FTAA), could change the toxicity of Aβ1–42 by comparing its behavior with that of p-FTAA. Moreover, we investigated the effects on toxicity when Aβ with the Arctic mutation (AβArc) was aggregated with both LCOs. Cell viability assays on SH-SY5Y neuroblastoma cells demonstrated that h-FTAA has a stronger impact on Aβ1–42 toxicity than does p-FTAA. Interestingly, h-FTAA, but not p-FTAA, rescued the AβArc-mediated toxicity. Aggregation kinetics and binding assay experiments with Aβ1–42 and AβArc when aggregated with both LCOs showed that h-FTAA and p-FTAA either interact with different species or affect the aggregation in different ways. In conclusion, h-FTAA protects against Aβ1–42 and AβArc toxicity, thus showing h-FTAA to be a useful tool for improving our understanding of the process of Aβ aggregation linked to cytotoxicity.
Highlights
The prevailing opinion is that prefibrillar β-amyloid (Aβ) species, rather than end-stage amyloid fibrils, cause neuronal dysfunction in Alzheimer’s disease, the mechanisms behind Aβ neurotoxicity remain to be elucidated
We recently demonstrated that pentamer formyl thiophene acetic acid (p-FTAA) can interact with Aβ1−42 and manipulate the aggregation process, leading to reduced cell toxicity.[13]
We discovered that heptamer formyl thiophene acetic acid (h-FTAA) could rescue Aβ1−42-mediated toxicity more effectively than p-FTAA and that h-FTAA conferred protection when aggregated with Aβ with the Arctic mutation (AβArc), which most probably is due to stronger binding of AβArc to h-FTAA than to p-FTAA
Summary
The prevailing opinion is that prefibrillar β-amyloid (Aβ) species, rather than end-stage amyloid fibrils, cause neuronal dysfunction in Alzheimer’s disease, the mechanisms behind Aβ neurotoxicity remain to be elucidated. We investigated whether an LCO, heptamer formyl thiophene acetic acid (h-FTAA), could change the toxicity of Aβ1−42 by comparing its behavior with that of p-FTAA. We investigated the effects on toxicity when Aβ with the Arctic mutation (AβArc) was aggregated with both LCOs. Cell viability assays on SH-SY5Y neuroblastoma cells demonstrated that h-FTAA has a stronger impact on Aβ1−42 toxicity than does p-FTAA. The formed extracellular senile plaques have long been considered the main toxic agent, but there is a growing consensus that smaller soluble Aβ aggregates such as oligomers exert neurotoxic activity because these correlate better with disease progression.[1,2] The Aβ peptides are proteolytically cleaved from the amyloid precursor protein (APP) by β-secretase and γ-secretase into mainly Aβ1−40 or Aβ1−42. The LCOs p-FTAA (pentamer formyl thiophene acetic acid) and h-FTAA, with two additional thiophene units (heptamer formyl thiophene acetic acid)
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