Proteolytically Stable ααγ-Hybrid Peptides Inhibit the Aggregation and Cytotoxicity of Aß42.

The recent approval of antibody-based therapy for targeting the clearance of amyloid plaques fuels the research in designing small molecules and peptide inhibitors to target the aggregation of Aß-peptides. Here, we report that the 15-residue ααγ-hybrid peptide not only inhibits the aggregation of soluble Aß42 into fibrils but also disintegrates the aggregated Aß42 fibrils into smaller assemblies. Further, the hybrid peptide completely rescues neuronal cells from the toxicity of Aß42 at equimolar concentrations. The shorter 10- and 12-mer peptides showed weak aggregation inhibition activity, while the fully hydrophobic 15-mer ααγ-hybrid peptide analogue showed no aggregation inhibition activity. Further, the 15-mer ααγ-hybrid peptide showed resistance against trypsin digestion and also nontoxic to the neuronal cells. The CD revealed that the peptide upon interaction induces a helix-type conformation in the Aß42. This is in sharp contrast to the ß-sheet conformation of Aß42 upon incubation. The two-dimensional-NMR (2D-NMR) analysis revealed a large perturbation in the chemical shifts of residues at the N-terminus. The presence of 15-mer peptide at an equimolar concentration of Aß42 showed less tendency for aggregation and also exhibited nontoxicity to the neuronal cells. The results reported here may be useful in designing new therapeutics for Alzheimer's disease.

Structural analysis of the AICD central 12 residue peptide stretch and its interactions with metals and polyphenols, as a potential drug target for AD.

Structural analysis of the central 12 residue stretch of Amyloid precursor protein Intracellular Domain (AICD16-27: T-S-I-H-H-G-V-V-E-V-D-A) was carried out by NMR and homology modeling. Further, metal and polyphenol interactions were also carried out for these 12 residues stretch, as it contains two critical Histidine residues, which were observed to be perturbed via NMR. A full length 57 residues AICD model was generated via computational methods, to ascertain its overall conformation, as the entire structure was unavailable. An overlay of this AICD entire model with the full length Aß-42 structure matched well, implying similar properties. Docking studies with metals and polyphenols indicated involvement of the key Histidine residues highlighting their roles towards neurodegeneration and AD pathophysiology.Communicated by Ramaswamy H. Sarma.

A cationic amphiphilic peptide chaperone rescues Aß42 aggregation and cytotoxicity.

Directing Aß42 to adopt a conformation that is free from aggregation and cell toxicity is an attractive and viable strategy to design therapeutics for Alzheimer's disease. Over the years, extensive efforts have been made to disrupt the aggregation of Aß42 using various types of inhibitors but with limited success. Herein, we report the inhibition of aggregation of Aß42 and disintegration of matured fibrils of Aß42 into smaller assemblies by a 15-mer cationic amphiphilic peptide. The biophysical analysis comprising thioflavin T (ThT) mediated amyloid aggregation kinetic analysis, dynamic light scattering, ELISA, AFM, and TEM suggested that the peptide effectively disrupts Aß42 aggregation. The circular dichroism (CD) and 2D-NMR HSQC analysis reveal that upon interaction, the peptide induces a conformational change in Aß42 that is free from aggregation. Further, the cell assay experiments revealed that this peptide is non-toxic to cells and also rescues the cells from the toxicity of Aß42. Peptides with a shorter length displayed either weak or no inhibitory effect on Aß42 aggregation and cytotoxicity. These results suggest that the 15-residue cationic amphiphilic peptide reported here may serve as a potential therapeutic candidate for Alzheimer's disease.