Peptide-based inhibitors of Tau aggregation as a potential therapeutic for Alzheimer's disease and other Tauopathies

Aggidis, A.; Chatterjee, S.; Townsend, D.; Fullwood, N. J.; Ruiz Ortega, E.; Tarutani, A.; Hasegawa, M.; Lucas, H.; Mudher, A.; Allsop, D.

doi:10.1101/2021.06.04.447069

bioRxiv · 10.1101/2021.06.04.447069

Peptide-based inhibitors of Tau aggregation as a potential therapeutic for Alzheimer's disease and other Tauopathies

Aggidis, A.·Chatterjee, S.·Townsend, D.·Fullwood, N. J.·Ruiz Ortega, E.·Tarutani, A.·Hasegawa, M.·Lucas, H.·Mudher, A.·Allsop, D.

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Abstract

There are currently no disease altering drugs available for Tauopathies such as Alzheimers disease, which alone is predicted to affect ~88 million people worldwide by 2050. As Tau aggregation underpins its toxicity, aggregation inhibitors are likely to have disease-modifying potential. Guided by in-silico mutagenesis studies, we developed a potent retro-inverso peptide inhibitor of Tau aggregation, RI-AG03 [Ac-rrrrrrrrGpkyk(ac)iqvGr-NH2], based on the 306VQIVYK311 hotspot. Aggregation of recombinant Tau was reduced by >90% with equimolar RI-AG03 and no fibrils were observed by EM. When added during the growth phase, RI-AG03 blocked seeded aggregation. Fluorescein-tagged RI-AG03 efficiently penetrated HEK-293 cells over 24 hours and was non-toxic at doses up to 30 M. In transgenic Drosophila, RI-AG03 significantly improves neurodegenerative and behavioural phenotypes caused by expression of human Tau. Collectively this shows that RI-AG03 can effectively reduce Tau aggregation in vitro and block aggregation-dependent phenotypes in vivo, raising possibilities for exploring its translational potential.

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Aggidis, A., Chatterjee, S., Townsend, D., Fullwood, N. J., Ruiz Ortega, E., Tarutani, A., Hasegawa, M., Lucas, H., Mudher, A., Allsop, D.. 2021-06-05. Peptide-based inhibitors of Tau aggregation as a potential therapeutic for Alzheimer's disease and other Tauopathies. https://doi.org/10.1101/2021.06.04.447069

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