A natural heptameric peptide exhibits multifaceted inhibitory role in
the fibrillation pathway of amyloid-beta
Abstract
Background and Purpose Alzheimer’s disease (AD) pathogenesis involves
amyloid-β (Aβ) aggregation where the intermediate oligomers are
considered the prime toxic species. Here, we aimed to identify an
effective peptide sequence from a medicinal plant-derived enzyme having
anti-amyloidogenic properties against Aβ. Experimental Approach LC-MS/MS
followed by computational analysis identified the active peptide (termed
here as Pactive). Visualization techniques along with biophysical and
biochemical approaches were used to determine the anti-amyloidogenic
potency of the purified enzyme and peptides identified from the enzyme.
Cytotoxicity was measured on SHSY-5Y cell lines. Interaction studies
were done with bio-layer interferometry (BLI) and bio-stability of the
peptide was assessed by NMR. Pactive induced conformational alterations
of Aβ monomer and oligomers was determined with DSC and NMR. Key Results
A small heptameric peptide (Pactive) identified form a medicinal
plant-derived fibrinolytic enzyme proved to be a multifunctional
inhibitor against Aβ aggregation. The results suggested that Pactive
arrests Aβ molecules in non-toxic off-pathway oligomers that can no
longer participate in the cytotoxic fibrillation pathway.
Mechanistically, Pactive binding induces conformational alterations in
the Aβ molecule, thus modulating its hydrophobicity, one of the key
players in inducing aggregation. Conclusions and Implications The study
identified a natural peptide Pactive (GFLLHQK) that displays potential
anti-amyloidogenic properties against Aβ aggregation. The bio-stability
of Pactive in human blood serum as well as its non-toxic nature makes it
a promising therapeutic candidate against Alzheimer’s, for which no
disease-modifying treatments are available till date.