A cationic amphiphilic peptide chaperone rescues Aβ₄₂ aggregation and cytotoxicity

Abstract

Directing Aβ42 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...

Proteolytically Stable ααγ-Hybrid Peptides Inhibit the Aggregation and Cytotoxicity of Aβ42

“…10 4 cells were seeded in each well in 96-well plates and incubated at 37 °C up to 24 h. The 3,(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) experiments were performed on SHSY5Y cell line as reported earlier. 40,41 Briefly, after 24 h of incubation of cells at 37 °C in a 96well plate, the medium was removed and further cells were incubated with the solution containing 10 μM of Aβ 42 aggregates diluted in DMEM/F12 medium. To check the effect of P1 on the cytotoxicity of Aβ 42 aggregates, 10 μM of Aβ 42 was mixed with 1, 3, 5, 10, and 30 μM concentrations of P1, 10 μM of P2, and 10 μM of P3 and incubated at 37 °C for up to 12 h prior to the treatment of cells.…”

“…15 N-Aβ 42 from the literature were used to identify all cross-peaks. 41,50,51 The addition of peptide P1 to the 15 N-Aβ 42 sample was less than 2% dilution, and the dilution factor was corrected while calculating the perturbation in the chemical shifts of 1 H− 15 N resonances. The NMR spectra were processed and analyzed by using TOPSIN software.…”

“…A fresh sample of 15 N-Aβ 42 (40 μM) 1 H– 15 N HSQC NMR experiments was performed using NaPi buffer (20 mM) having pH 7.4 in the absence and presence of 2 equiv of P1 at 283 K with a cryoprobe (Aβ 42 :peptide P1 ; 1:2). Previously assigned 1 H– 15 N HSQC NMR spectra of 15 N-Aβ 42 from the literature were used to identify all cross-peaks. ,, The addition of peptide P1 to the 15 N-Aβ 42 sample was less than 2% dilution, and the dilution factor was corrected while calculating the perturbation in the chemical shifts of 1 H– 15 N resonances. The NMR spectra were processed and analyzed by using TOPSIN software.…”

“…We have been interested in designing Aβ aggregation inhibitors using short peptides. , Recently, we showed the inhibition of Aβ 42 aggregation by cationic amphiphilic α-peptides . We have been working in the area of foldamers consisting of α,γ-hybrid peptides − and demonstrated that hybrid peptides composed of alternating 1:1 α and γ-amino acid adopt a 12-helical conformation, while 2:1 α- and γ-amino acids (ααγ-hybrid peptides) adopt a 10/12-helical conformation with different side-chain orientations .…”

“…40,41 Recently, we showed the inhibition of Aβ 42 aggregation by cationic amphiphilic αpeptides. 41 We have been working in the area of foldamers consisting of α,γ-hybrid peptides 42−44 and demonstrated that hybrid peptides composed of alternating 1:1 α and γ-amino acid adopt a 12-helical conformation, 45 while 2:1 αand γamino acids (ααγ-hybrid peptides) adopt a 10/12-helical conformation with different side-chain orientations. 46 In the case of ααγ-hybrid peptide 10/12-helices, the amino acid side chains are projected at three sides of the helix.…”