title: Microtubule stabilising peptides rescue tau phenotypes in-vivo.
abstract: The microtubule cytoskeleton is a highly dynamic, filamentous network underpinning cellular structure and function. In Alzheimer's disease, the microtubule cytoskeleton is compromised, leading to neuronal dysfunction and eventually cell death. There are currently no disease-modifying therapies to slow down or halt disease progression. However, microtubule stabilisation is a promising therapeutic strategy that is being explored. We previously investigated the disease-modifying potential of a microtubule-stabilising peptide NAP (NAPVSIPQ) in a well-established Drosophila model of tauopathy characterised by microtubule breakdown and axonal transport deficits. NAP prevented as well as reversed these phenotypes even after they had become established. In this study, we investigate the neuroprotective capabilities of an analogous peptide SAL (SALLRSIPA). We found that SAL mimicked NAP's protective effects, by preventing axonal transport disruption and improving behavioural deficits, suggesting both NAP and SAL may act via a common mechanism. Both peptides contain a putative 'SIP' (Ser-Ile-Pro) domain that is important for interactions with microtubule end-binding proteins. Our data suggests this domain may be central to the microtubule stabilising function of both peptides and the mechanism by which they rescue phenotypes in this model of tauopathy. Our observations support microtubule stabilisation as a promising disease-modifying therapeutic strategy for tauopathies like Alzheimer's disease.
authors.affiliation: Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, Building 85, University of Southampton, Southampton, SO17 1BJ, UK.
authors.forename: Shmma
authors.initials: S
authors.lastname: Quraishe
authors.affiliation: Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, Building 85, University of Southampton, Southampton, SO17 1BJ, UK.
authors.forename: Megan
authors.initials: M
authors.lastname: Sealey
authors.affiliation: Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, Building 85, University of Southampton, Southampton, SO17 1BJ, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Cranfield
authors.affiliation: Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, Building 85, University of Southampton, Southampton, SO17 1BJ, UK.
authors.forename: Amritpal
authors.initials: A
authors.lastname: Mudher
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D030801:Animals, Genetically Modified; D001370:Axonal Transport / Q000187:drug effects / Q000235:genetics; D004331:Drosophila melanogaster; D006801:Humans; D008870:Microtubules / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000494:pharmacology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D010455:Peptides; D016875:tau Proteins