Cristina Pubill Ulldemolins – University of Sussex
Amrit Mudher – University of Southampton
Sumeet Mahajan – University of Southampton
Louise Serpell – University of Sussex
Alzheimer’s Disease (AD) is the most common form of dementia and it is characterised by the deposition of amyloid-β (Aβ) and Tau in extracellular plaques and intracellular neurofibrillary tangles .
Alzheimer’s Disease (AD) is the most common form of dementia and it is characterised by the deposition of amyloid-β (Aβ) and Tau in extracellular plaques and intracellular neurofibrillary tangles . Currently, there is no cure for AD and very few therapies are available to alleviate symptoms. Our collaborators have recently shown that leptin peptides are potential therapeutics in the fight against AD . This provided the first compelling evidence for the neuroprotective effects of small, leptin-derived peptides as disease modifying therapies. However, the therapeutic value of leptin peptides per se are limited as they cannot be administered in tablet form
since they are rapidly broken down by the digestive system. It is therefore important to investigate the neuroprotective potential of synthetic leptin-peptide analogues. We propose to use an iterative approach, combining synthetic and computational chemistry with in vitro and in vivo bioassays, to design novel bioactive leptin-based peptides with improved pharmacokinetics and resistance to degradation. In this context, recent experimental evidence has stablished that leptin (the whole protein), reduces TAU pathology in a mouse model of AD . Therefore, we have chosen to assess the impact of leptin-peptides and analogues in TAU aggregation in our bioassays, as well as assessing their impact on Aβ mediated toxicity. Together we will thus have investigated the neuroprotective effect of leptin based peptides against both Tau and Amyloid pathology. Objective 1) Synthesis and computational modelling—towards understanding of the minimal ligand and design of leptin peptide analogues with improved pharmacokinetics. Using an in-house peptide synthesiser, we will synthesise analogues of the key hexa- and nona-leptin peptides, which form the basis of a recent patent (US# 62/553050) by our collaborators, with improved predicted affinity, stability and bioavailability. Complementary state-of the-art computational calculations will be performed to inform reaction design and development of leptin peptides and leptin analogues. Objective 2) In vitro tests (in collaboration with Prof Serpell at Sussex University)—Evaluating the bioactivity of novel chemically modified leptin peptides in assays to establish their neuroprotective properties. We will test whether the peptide analogues synthesized in Objective 1) mirror the neuroprotective actions of leptin per se, and native leptin peptides, by attenuating the toxic effects of Aβ on neuronal viability. Lead peptides will be put forward for further biochemical, electrophysiological and in vitro testing to establish the lead neuroprotective and neuroactive compounds [2 and 4]. Establishing how native and chemically modified leptin peptides influence the self-assembly of tau proteins. We will examine the effect of the modified leptin peptides on the self-assembly kinetics, structure and toxicity of Tau using established methodologies (e.g. thioflavine T assays, circular dichroism, transmission electron microscopy) to follow the self-assembly and modulation of tau aggregation . Objective 3) In vivo test- Assessment of the impact on Tau aggregation. Using the Mudher Group’s expertise, the most potent peptide candidates identified in Objective 2) will be tested on their ability to reduce tau aggregation in an in vitro assay  This will be followed by analysing the impact of the most promising peptides on tau aggregation and tau-mediated phenotypes in two Drosophila models of tauopathy . Findings
will be verified by crossing tauopathy flies with leptin-deficient flies which should not therefore develop the tau phenotypes or aggregation. The successful implementation of this multidisciplinary and ambitious project will provide insight into the modulation of the leptin system and understanding of their interactions with both Amyloid and Tau protein will open new therapeutic avenues for AD and other dementia diseases. References:  D.J. Selkoe, et al., Ann. N. Y. Acad. Sci. 2000, 924, 17;  G.H. Doherty, et al., Cereb Cortex, 2017, 27(10), 4769;  M.P. Murphy, Neuroscience, 2016, 19, 162;  G.H. Doherty, et al., Neurobiol. Aging. 2013, 34(1), 226;  L.C. Serpell, et al. J. Mol. Biol., 2018, 430, 4119;  G. Devitt, et al., ACS Chem Neurosci. 2019, 10(11), 4593;  M.A. Sealey, et al., Neurobiol. Dis., 2017, (105)74