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Emtins : novel peptides derived from metallothionein-II as potential therapeutics in Alzheimer's disease

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Eaton, ED (2016) Emtins : novel peptides derived from metallothionein-II as potential therapeutics in Alzheimer's disease. PhD thesis, University of Tasmania.

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Abstract

Alzheimer’s disease (AD) is a common neurodegenerative disease that is characterised by the
extracellular accumulation of plaques, comprised predominantly of the β-amyloid (Aβ)
peptide. These Aβ peptides have demonstrated toxic effects on neurons under a variety of
experimental conditions. Metallothioneins (MTs) are a family of low molecular weight, metal
binding proteins that have demonstrated neuroprotective and neuroregenerative properties.
Recently MTs have been shown in neuronal cultures to be protective against a toxic, copperbound
form of Aβ (CuAβ). MTs have been proposed as a potential therapeutic for the treatment of AD, however, MT does not cross the blood brain barrier (BBB) to an appreciable degree, which limits its capacity as an AD therapeutic. More recently, synthetic peptides based on the MT sequence, termed emtins, have been developed. Emtins have not only reproduced some of the properties of MT but, importantly, one peptide has been demonstrated to cross the mouse BBB, indicating that emtins may represent a novel therapeutic for the treatment of AD.
This thesis investigates the capacity of two emtins, EmtinB and EmtinAc, to protect cultured rat
hippocampal neurons against CuAβ with the aim of determining the most effective peptide for
ongoing studies. EmtinB was the more effective of the two emtins tested in this toxicity model.
Furthermore, in a comparison of two EmtinB forms; a tetrameric, 4 -peptide form and a
dimeric, 2-peptide form, the dimeric EmtinB peptide was shown to be considerably more
protective than the tetrameric form.
Three potential mechanisms by which EmtinB might protect cultured rat neurons against CuAβ
were investigated: removal of copper from CuAβ to prevent formation of free radicals, direct
scavenging of free radicals by EmtinB, and improved neuronal survival via activation of the LRP
family of receptors. While no conclusion was reached on its primary mechanistic action, this
thesis will show that EmtinB is able to bind metals such as copper and zinc, and can remove copper from the CuAβ complex. Further investigations into mechanism show that EmtinB is also able to protect cultured rat neurons against hydrogen peroxide (which can be generated by CuAβ) and that EmtinB is unable to protect against CuAβ in the presence of an inhibitor of the LRP family of receptors suggesting that EmtinB may potentially be interacting with hippocampal neurons via the LRP family of receptors.
The in vivo protective capacity of EmtinB was also investigated in this thesis using the
APPswe/PS1Δ E9 mouse model of AD. In this model, EmtinB treatment was shown to improve
cognitive outcomes, as measured by Y-maze, and also reduced astroglial activation, as
measured by GFAP levels, but did not reduce levels of activated microglia. Although EmtinB
treatment appeared to reduce plaque load, these changes were not statistically significant and
soluble levels of Aβ remained unchanged.
This thesis investigates the activity of emtin peptides to protect cultured hippocampal neurons
against a toxic copper-bound form of Aβ and the ability of EmtinB to reduce cognitive deficits
and alter pathological markers of AD in the APPswe/PS1ΔE9 mouse model of AD. Emtin peptides have demonstrated beneficial outcomes in both in vivo and in vitro models of AD, but as yet a single definitive mechanism cannot be ascribed.

Item Type: Thesis (PhD)
Keywords: Emtins, Metallothioneins, Alzheimer's disease, Peptide therapy
Copyright Information:

Copyright 2016 the Author

Date Deposited: 04 Nov 2016 05:07
Last Modified: 23 Mar 2017 03:13
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