Hydrophobic C-Terminal Peptide Analog Aβ31-41 Protects the Neurons from Aβ-Induced Toxicity

Spontaneous aggregation of amyloid beta (A beta) leads to the formation of neurotoxic senile plaque considered as the most crucial event in Alzheimer's disease (AD) progression. Inhibition or disruption of this deadly aggregate formation is one of the most efficient strategies for the development of potential therapeutics, and extensive research is in progress by various research groups. In this direction, the development of a peptide analogous to that of the native A beta peptide is an attractive strategy. Based on this rationale, beta-sheet breakers were developed from the A beta central hydrophobic core. These peptide derivatives will bind to the full length of the parent A beta and interfere in self-recognition, thereby preventing the folding of the A beta peptide into cross beta-sheet neurotoxic aggregates. However, this approach is effective in the inhibition of fibrillar aggregation, but this strategy is ineffective in the A beta neurotoxic oligomer formation. Therefore, an alternative and efficient approach is to use the A beta peptide analogous to the C-terminal region, which arbitrates fibrillation and oligomerization. Herein, we developed the A beta C-terminal fragment (ACT-1 to ACT-7) for inhibition of oligomerization as well as fibrillar aggregation. Screening of these seven peptides resulted in an efficient anti-A beta peptide aggregative agent (ACT-7), which was evaluated by the ThT assay peptide. The ThT assay reveals complete inhibition and showed significant neuroprotection of PC-12-derived neurons from A beta-induced toxicity and reduced cell apoptosis. Further, analysis using CD and FTIR spectroscopy reveals that the ACT-7 peptide efficiently inhibits the formation of the beta-sheet secondary structure content. HR-TEM microscopic analysis confirmed the inhibition of formation. Therefore, the inhibition of beta-sheet A beta fibrillary aggregation by the protease-stable ACT-7 peptide may provide a beneficial effect on AD treatment to control the A beta aggregates. Finally, we anticipate that our newly designed ACT peptides may also assist as a template molecular scaffold for designing potential anti-AD therapeutics.