Amyloid Fibril-Forming Hexapeptides Modulate the Immune Response and Reduce Symptoms in an Animal Model of Multiple Sclerosis (S14.002)

OBJECTIVE: To determine the immune pathways modulated by amyloid fibril-forming peptides composed of six amino acids that have been found to be anti-inflammatory and therapeutic in an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). BACKGROUND: Our earlier work showed that amyloid fibril formation of a small peptide corresponding to residues 73-92 from the small heat shock protein alpha B crystallin (HspB5) correlated with chaperone activity and amelioration of EAE. However, exchange of one hydrophobic amino acid at position 77, 79, or 81 with a lysine disrupted amyloid formation, chaperone function, and therapeutic efficacy of the peptide. To eliminate the toxicity of amyloid fibrils formed by larger peptides and proteins, we used the minimum number of amino acids capable of forming amyloid fibrils. Peptides composed of six amino acids that form amyloid fibrils were shown to have chaperone activity and were therapeutic in EAE. RESULTS: The levels of IL-6, IL-2, TNF alpha, and IFN gamma were all decreased following treatment with the hexapeptide tau 623-628. We also show that tau 623-628 induces type I interferon (IFN), which is a treatment in MS and indicates a distinct effect not seen in HspB5 treatment. Tau 623-628 was therapeutic in Th1 adoptively transferred EAE, but ineffective in Th17 adoptively transferred EAE, which corresponds with the observation that type I IFN is beneficial in Th1 EAE, but not in Th17 EAE (Axtell et al., Nat Med 2010; 16: 406-412). Amylin 28-33, a polar, non-ionizable peptide, induces very low levels of type I IFN and is therapeutic in Th17 EAE, indicating other immune pathways play a role in amelioration of EAE. CONCLUSIONS: The mode of action of the amyloid-forming hexapeptides is similar to HspB5 in its capacity to bind pro-inflammatory proteins in the plasma, which could have pleiotropic effects including the reduction of pro-inflammatory cytokines. However, the amyloidogenic peptides also modulate diverse immunological pathways, which can differ based upon the composition of the hexapeptides.