Inhibition of the Aggregation and Toxicity of the Minimal Amyloidogenic Fragment of Tau by Its Pro‐Substituted Analogues

Abstract

Inhibiting the toxic aggregation of amyloid-β and the tau protein, the key pathological agents involved in Alzheimer's, is a leading approach in modulating disease progression. Using an aggregative tau-derived model peptide, Ac-PHF6-NH , the substitution of its amino acids with proline, a known efficient β-breaker, is shown to reduce self-assembly. This effect is attributed to the steric hindrance created by the proline substitution, which results in disruption of the β-sheet formation process. Moreover, several of the proline-substituted peptides inhibit the aggregation of Ac-PHF6-NH amyloidogenic peptide. Two of these modified inhibitors also disassemble pre-formed Ac-PHF6-NH fibrils and one inhibits induced cytotoxicity of the fibrils. Taken together, these lead β-breaker peptides may be developed into novel Alzheimer's disease therapeutics.

Elucidating Tau function and dysfunction in the era of cryo-EM

“…The side chain of Lys 311 equally points outside, probably through interaction with the negatively charged heparin. Indeed, introducing a negative charge at this position was previously found to reduce aggregation in the heparin-induced aggregation assay (60). Only in the heparin-induced 3R-Tau fibrils, where two Tau molecules stack to make a fibrillary structure (rather than one single Tau molecule bending over itself to form a protofilament), do the PHF6 peptide sequences on the molecules face one another (17).…”

Modulation of aggregation with an electric field; scientific roadmap for a potential non-invasive therapy against tauopathies

“…1 Although this number is expected to increase to 132 million by 2050, there is no clinically approved therapy to cure or retard its progression. 1 Promising therapeutic strategies under research include native state stabilisation or brillation inhibition using small molecules, 2-6 immunotherapy, 7,8 peptide or peptidomimetics, [9][10][11][12][13][14][15][16][17][18] nanoparticles, 19,20 transient metals, [21][22][23][24] supramolecular inhibition of brillation 25,26 and sequestering the monomeric form of the peptide. 27 Nucleation-dependent aggregation is one of the most accepted models for the formation of amyloid brils.…”

“…37,38 The instigation of tau protein aggregation, linked with over 20 neurological disorders known as tauopathies, has been ascribed to the presence of two hexapeptide motifs "Ac-VQIVYK-am (PHF6) and Ac-VQIINK-am (PHF6*)". 16 These motifs are found in R2 and R3 repeat domains of tau protein and have been reported to be critical for conferring the strong aggregation tendency to tau protein. 39 Therefore, these peptide segments are regarded as the ideal model for assessing the potential therapies for the AD.…”

Tryptophan-galactosylamine conjugates inhibit and disaggregate amyloid fibrils of Aβ42 and hIAPP peptides while reducing their toxicity

“…π-π stacking, rather than mere hydrophobicity, was shown to provide energy, order and directionality to promote amyloid assembly [29][30][31] . Based on these insights, peptide-based inhibitors were designed to contain aromatic residues whose side chains can intercalate the target amyloid aggregate and partially replace the original amino acids in π-π stacking [32][33][34][35][36] . Along the same lines, small aromatic molecules, e.g.…”