Spontaneous aggregation of amyloid
beta (Aβ) 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 Aβ
peptide is an attractive strategy. Based on this rationale, β-sheet
breakers were developed from the Aβ central hydrophobic core.
These peptide derivatives will bind to the full length of the parent
Aβ and interfere in self-recognition, thereby preventing the
folding of the Aβ peptide into cross β-sheet neurotoxic
aggregates. However, this approach is effective in the inhibition
of fibrillar aggregation, but this strategy is ineffective in the
Aβ neurotoxic oligomer formation. Therefore, an alternative
and efficient approach is to use the Aβ peptide analogous to
the C-terminal region, which arbitrates fibrillation and oligomerization.
Herein, we developed the Aβ 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-Aβ
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 Aβ-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 β-sheet secondary structure content. HR-TEM
microscopic analysis confirmed the inhibition of formation. Therefore,
the inhibition of β-sheet Aβ fibrillary aggregation by
the protease-stable ACT-7 peptide may provide a beneficial effect
on AD treatment to control the Aβ aggregates. Finally, we anticipate
that our newly designed ACT peptides may also assist as a template
molecular scaffold for designing potential anti-AD therapeutics.