The luminescent oligothiophene p-FTAA converts toxic Aβ1-42 species into nontoxic amyloid fibers with altered properties

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Abstract

Aggregation of the amyloid-β peptide (Aβ) in the brain leads to the formation of extracellular amyloid plaques, which is one of the pathological hallmarks of Alzheimer disease (AD). It is a general hypothesis that soluble prefibrillar assemblies of the Aβ peptide, rather than mature amyloid fibrils, cause neuronal dysfunction and memory impairment in AD. Thus, reducing the level of these prefibrillar species by using molecules that can interfere with the Aβ fibrillation pathway may be a valid approach to reduce Aβ cytotoxicity. Luminescent-conjugated oligothiophenes (LCOs) have amyloid binding properties and spectral properties that differ when they bind to protein aggregates with different morphologies and can therefore be used to visualize protein aggregates. In this study, cell toxicity experiments and biophysical studies demonstrated that the LCO p-FTAA was able to reduce the pool of soluble toxic Aβ species in favor of the formation of larger insoluble nontoxic amyloid fibrils, there by counteracting Aβ-mediated cytotoxicity. Moreover, p-FTAA bound to early formed Aβ species and induced a rapid formation of β-sheet structures. These p-FTAA generated amyloid fibrils were less hydrophobic and more resistant to proteolysis by proteinase K. In summary, our data show that p-FTAA promoted the formation of insoluble and stable Aβ species that were nontoxic which indicates that p-FTAA might have therapeutic potential.

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Civitelli, L., Sandin, L., Nelson, E., Khattak, S. I., Brorsson, A. C., & Kågedal, K. (2016). The luminescent oligothiophene p-FTAA converts toxic Aβ1-42 species into nontoxic amyloid fibers with altered properties. Journal of Biological Chemistry, 291(17), 9223–9243. https://doi.org/10.1074/jbc.M115.696229

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