Untangled - peptide-based inhibitors of tau aggregation as a potential treatment for Alzheimer's disease

Allsop, David and Aggidis, Anthony and Fullwood, Nigel James and Taylor, Mark Neville and Foulds, Penelope and Vincent, Shoona and Dale, Mark (2018) Untangled - peptide-based inhibitors of tau aggregation as a potential treatment for Alzheimer's disease. Journal of Prevention of Alzheimer's Disease, 5 (Suppl ). S15-S16. ISSN 2426-0266

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Background Neurofibrillary tangle (NFT) formation within neuronal cells is one of the two main pathological hallmarks of Alzheimer’s disease (AD). The extent of tangle formation in the brain shows a better correlation with clinical disease severity than that of amyloid plaque formation, although Aβ aggregation is likely to precede and induce tangle formation [1]. Clinical trials involving immunological removal of β-amyloid (Aβ) from the brain, or the use of secretase inhibitors to limit production of Aβ, have so far shown little or no improvement in clinical outcome measures in mild cognitive impairment (MCI) and AD patients, and this type of therapy may require very early intervention in the course of the disease. Inhibition of tau aggregation, or dual inhibition of amyloid and tau, could provide a better treatment for more advanced disease. We have previously developed very effective small peptide and peptide-liposome inhibitors of Aβ aggregation, and have achieved blood-brain barrier penetration, reduction in amyloid plaque load, inhibition of oligomer formation, reduction in oxidation and inflammation, and prevention of memory loss, in transgenic mouse models [2-4]. Here, we describe a similar approach to development of peptide-based inhibitors of tau aggregation. Objectives Our objective is to prevent tau aggregation based on the rational design of inhibitory peptides and peptide derivatives focussed around the self-binding motifs of tau protein - with additional solubilising residues, and the addition of cell-penetrating and brain-penetrating peptide transit sequences. Further work will involve covalent attachment of these peptides to the surface of nanoliposomes, along with the development of a dual-acting liposome that inhibits both Aβ and tau aggregation. Methods To optimise the tau binding sequence, we tested a series of peptides, over a number of iterations, for their effects on tau aggregation, and then looked at the effects of retro-inversion and N-methylation on the resulting optimal peptide, in order to increase its stability. The misfolding and aggregation of recombinant tau Δ250 (at 20 µM in the presence of 5 µM heparin) were examined in the presence of various concentrations of these inhibitory peptides, using thioflavin fluorescence, Congo red polarization microscopy, CD spectroscopy and negative stain EM. Results The retro-inverted form of the optimal peptide, RIAG03, was an effective inhibitor of tau aggregation, with an IC50 of around 7.8 µM against 20 µM of tau Δ250. Examination by negative stain EM showed that an equimolar concentration of this inhibitor almost completely blocked tau fibril formation. Various control peptides (e.g. with a scrambled binding sequence, or the transit peptide alone) were ineffective. RIAG03 also inhibited β-sheet formation, as determined by CD spectroscopy and Congo red binding. The solubilising residues incorporated into the amino acid sequence of RIAG03 prevented self-aggregation of this inhibitor peptide. Conclusions We have identified an effective cell-penetrating and stabilized inhibitor of tau aggregation for further preclinical development and testing in cell and animal models. One of our next steps will be to attach RIAG03 to our nanoliposomes to give a multivalent inhibitor that should have enhanced potency [4]. One of our main objectives is to attach inhibitory peptides directed at both Aβ and tau to the same liposomes, to produce a dual aggregation inhibitor. Due to the complex heterogeneous aetiology of AD, It is becoming increasingly apparent that combination therapies may be required, and liposomes are a biocompatible and highly flexible vehicle for achieving this. [1] Hardy J. & Allsop D. (1991) Trends Pharmacol. Sci. 12, 383-388; [2] Taylor M., et al. (2010) Biochemistry 49, 3261–3272; [3] Parthsarathy V., et al. (2013) PLoS ONE 2013;8(1): e54769; [4] Gregori M., et al. (2017) Nanomed: Nanotech. Biol. Med. 13, 723-732.

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Journal Article
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Journal of Prevention of Alzheimer's Disease
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04 Jan 2019 04:24
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22 Nov 2022 06:51