Ke Hou, Hope Pan, Hedieh Shahpasand-Kroner, Carolyn Hu, Romany Abskharon, Paul Seidler, Marisa Mekkittikul, Melinda Balbirnie, Carter Lantz, Michael R Sawaya, Joshua L Dolinsky, Mychica Jones, Xiaohong Zuo, Joseph A Loo, Sally Frautschy, Greg Cole, David S Eisenberg
Amyloid fibrils of tau are increasingly accepted as a cause of neuronal death and brain atrophy in Alzheimer's disease (AD). Diminishing tau aggregation is a promising strategy in the search for efficacious AD therapeutics. Previously, our laboratory designed a six-residue, nonnatural amino acid inhibitor D-TLKIVW peptide (6-DP), which can prevent tau aggregation in vitro. However, it cannot block cell-to-cell transmission of tau aggregation. Here, we find D-TLKIVWC (7-DP), a d-cysteine extension of 6-DP, not only prevents tau aggregation but also fragments tau fibrils extracted from AD brains to neutralize their seeding ability and protect neuronal cells from tau-induced toxicity...
May 3, 2024: Science Advances