Reversal of temperature‐induced conformational changes in the amyloid‐beta peptide, Aβ40, by the β‐sheet breaker peptides 16–23 and 17–24

Background and purpose:  Aggregates of the protein amyloid‐beta (Aβ) play a crucial role in the pathogenesis of Alzheimer's disease (AD). Most therapeutic approaches to AD do not target Aβ, so determination of the factor(s) that facilitate aggregation and discovering agents that prevent aggregation have great potential therapeutic value. Experimental approach:  We investigated ex vivo the temperature‐sensitive regions of Aβ1–40 (Aβ40) and their interactions with octapeptides derived from sequences within Aβ40 –β‐sheet breaker peptides (βSBP) – using enzyme‐linked immunosorbent assay, and dot blot and far‐UV circular dichroism (CD) spectroscopy. We measured changes within the physiological limits of temperature, using antibodies targeting epitopes 1–7, 5–10, 9–14 and 17–21 within Aβ40. Key results:  Temperature‐dependent conformational changes were observed in Aβ40 at epitopes 9–14 and 17–21 at 36–38 and 36–40°C respectively. The βSBPs 16–23 and 17–24, but not 15–22 and 18–25, could inhibit the changes. Moreover, βSBPs 16–23 and 17–24 increased digestion of Aβ40 by protease K, indicating a decreased aggregation of Aβ40, whereas βSBPs 15–22 and 18–25 did not increase this digestion. CD spectra revealed that β‐sheet formation in Aβ40 at 38°C was reduced with βSBPs 16–23 and 17–24. Conclusions and implications:  The epitopes 9–14 and 17–21 are the temperature‐sensitive regions within Aβ40. The βSBPs, Aβ16–23 and 17–24 reversed temperature‐induced β‐sheet formation, and decreased Aβ40 aggregation. The results suggest that the 17–23 epitope of Aβ40 is crucially involved in preventing Aβ40 aggregation and consequent deposition of Aβ40 in AD brain.