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.
Show 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.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Tau protein aggregation associated with SARS-CoV-2 main protease 95%
- Selection of single domain anti-transferrin receptor antibodies for blood-brain barrier transcytosis using a neurotensin based assay and histological assessment of target engagement in a mouse model of Alzheimer's related amyloid-beta pathology 95%
- Screening of Tau Protein Kinase Inhibitors in a Tauopathy-relevant cell-based model of Tau Hyperphosphorylation and Oligomerization 95%
Similar papers in this journal
- Binding of different substrate molecules at the docking site and the active site of γ-secretase can trigger toxic events in sporadic and familial Alzheimer's disease 94%
- Identification of a cardiac glycoside exhibiting favorable brain bioavailability and potency for reducing levels of the cellular prion protein 92%
- Structural characterization of covalently stabilized human cystatin C oligomers 92%
Similar papers in this journal
- αS oligomers generated from polyunsaturated fatty acid and dopamine metabolite differentially interact with Aβ to enhance neurotoxicity 95%
- Glycated alpha-synuclein assemblies cause distinct Parkinsons disease pathogenesis in mice 93%
- Single molecule fingerprinting reveals different amplification properties of α-synuclein oligomers and preformed fibrils in seeding assay. 92%
Similar papers in this journal
- Computational insights into mechanism of AIM4-mediated inhibition of aggregation of TDP-43 protein implicated in ALS and evidence for in vitro inhibition of liquid-liquid phase separation (LLPS) of TDP-432C-A315T by AIM4. 96%
- Effect of Melatonin on Tau aggregation and Tau-mediated cell surface morphology 95%
- Identification of the three zinc-binding sites on Tau protein 93%
Similar papers in this journal
- Peptides derived from gp43, the most antigenic protein from Paracoccidioides brasiliensis, form amyloid fibrils in vitro: implications for vaccine development 93%
- PapRIV, a BV-2 microglial cell activating quorum sensing peptide 93%
- Conformation and membrane interaction studies of the potent antimicrobial and anticancer peptide palustrin-Ca 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.