Peptide-based inhibitors of Tau aggregation as a potential therapeutic for Alzheimer’s disease and other Tauopathies
Peptide-based inhibitors of Tau aggregation as a potential therapeutic for Alzheimer’s disease and other Tauopathies
There are currently no disease altering drugs available for Tauopathies such as Alzheimer’s 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 μM. 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.
Mudher, Amritpal
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119
Mudher, Amritpal
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119
Mudher, Amritpal
(2021)
Peptide-based inhibitors of Tau aggregation as a potential therapeutic for Alzheimer’s disease and other Tauopathies.
bioRxiv.
(doi:10.1101/2021.06.04.447069).
(In Press)
Abstract
There are currently no disease altering drugs available for Tauopathies such as Alzheimer’s 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 μM. 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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2021.06.04.447069v1.full
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Accepted/In Press date: 2021
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Local EPrints ID: 454449
URI: http://eprints.soton.ac.uk/id/eprint/454449
PURE UUID: a8b09e70-55ab-44a6-bcdf-e6a99d359415
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Date deposited: 09 Feb 2022 17:44
Last modified: 16 Mar 2024 15:34
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