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.

ADNP, a Microtubule Interacting Protein, Provides Neuroprotection Through End Binding Proteins and Tau: An Amplifier Effect

“…Together, these studies implicate ADNP/NAP in synaptic plasticity, involving EB proteins (Jaworski et al, 2009 ; Oz et al, 2014 ). While these results explained the previously observed NAP interaction with microtubules, bringing into focus the SIP motif (Gozes et al, 2016 ; Quraishe et al, 2016 ) and suggesting an amplifier effect at the microtubule tip, the molecular mechanism of increased Tau hyperphosphorylation, as a consequence of ADNP deficiency and protection by NAP against tauopathy (Vulih-Shultzman et al, 2007 ; Matsuoka et al, 2008 ; Shiryaev et al, 2009 ; Jouroukhin et al, 2013 ), still required further investigations.…”

A brain-penetrant triazolopyrimidine enhances microtubule-stability, reduces axonal dysfunction and decreases tau pathology in a mouse tauopathy model

“…The concept of utilizing MT-stabilizing agents to treat tauopathies has been discussed for some time [ 31 ], and our studies and those from others over the past several years have demonstrated the potential of this therapeutic strategy in tauopathy mouse models [ 24 – 27 , 32 , 61 , 62 ], as well as in other tau model systems [ 63 , 64 ]. Among traditional small molecule MT-stabilizing compounds, both EpoD and the abeotaxane, TPI-287, have progressed to Phase 1b clinical testing, where each was examined in short 2–3 month studies in AD and/or tauopathy patients.…”

Role of Tau as a Microtubule-Associated Protein: Structural and Functional Aspects

“…MT stabilizing peptides are another option chosen to restore MT stability (Quraishe et al, 2016; Mondal et al, 2018). A peptide such as the PS3 octapeptide was designed from the taxol-binding pocket of β-tubulin (Mondal et al, 2018).…”