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Targeting microtubule alterations in axon degeneration and Alzheimer’s Disease

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Hanson, KA ORCID: 0000-0002-4230-1827 2019 , 'Targeting microtubule alterations in axon degeneration and Alzheimer’s Disease', PhD thesis, University of Tasmania.

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Abstract

Microtubules are a key cytoskeletal element within the axon, which provide structure, shape and polarity to the neuron. They are important in numerous cellular processes, as they provide the platform for intracellular transport; moving organelles and secretory vesicles to synaptic terminals and are a major constituent for cell division. Disruption to microtubules has been implicated in a number of neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease and amyotrophic lateral sclerosis, which involve progressive loss of structure and function of neurons, leading to neuronal death in different regions of the nervous system. Although each of these diseases display different symptoms, some features may be shared across neurodegenerative diseases, such as axon degeneration, an active cellular process which can be initiated in pathological conditions resulting in synaptic impairment. Microtubule alterations have been implicated in mechanisms of axon degeneration. However, the alterations to microtubules in pathological conditions and the potential of modulating microtubules as a therapeutic target is currently unrealised. This thesis has examined the effect of microtubule stabilisation in a mouse model of AD and has investigated the changes to microtubules and microtubule-associated proteins within the axon following an excitotoxic insult, a pathological mechanism involved in several neurodegenerative diseases and injury. To examine microtubule alterations following excitotoxic insult, a compartmented primary mouse neuronal cell culture model was utilised and live imaging was used to monitor axon degeneration. Examination of alterations to microtubule associated proteins (MAPs) demonstrate that levels of tau and CRMP2 were significantly (p<0.05) increased after excitotoxic insult, but MAP1B levels were unchanged. Modifying the phosphorylation state of MAPs, using the PP2A inhibitor sodium selenate, which regulates their binding to microtubules, did not significantly affect the degeneration of axons. Examination of microtubule post-translational modifications demonstrated significantly (p<0.05) decreased acetylated tubulin levels, specifically in axons, whereas tyrosinated tubulin levels were unchanged. Trichostatin A, an HDAC6 inhibitor, was used in vitro to determine whether preventing loss of acetylated tubulin protects against axon degeneration. Primary cortical neurons treated with trichostatin A had significantly (p<0.05) increased acetylated tubulin levels within axons. Furthermore, live imaging results confirmed that neurons treated with trichostatin A had significantly (p<0.05) decreased axon degeneration following an excitotoxic insult. Previous studies have demonstrated a positive effect of microtubule stabilisation in mouse models of tau pathology. However, AD involves deposition of amyloid plaques in addition to tau pathology and the effect of microtubule stabilisation on amyloid and axon pathology in AD models is unknown. Therefore, an AD mouse model of amyloid deposition, the APP/PS1 mouse model was treated with the microtubule stabilising agent, epothilone D to determine the effect on plaque deposition, dystrophic neurite pathology and synapse alterations. Behavioural testing demonstrated significant changes in tests associated with anxious activity in APP/PS1 mice following epothilone D treatment. Biochemical analysis demonstrated that epothilone D had effects on the cytoskeleton with a significant (p<0.05) decrease in levels of phosphorylated neurofilaments in both the neocortex and hippocampus. However, epothilone D did not alter amyloid deposition or neurite dystrophy within the mouse neocortex. Together these results suggest that microtubule instability may be a key factor in axon degeneration pathways, and pharmacological manipulation of microtubules is a promising therapeutic target to prevent axon degeneration.

Item Type: Thesis - PhD
Authors/Creators:Hanson, KA
Keywords: Microtubules, axon degeneration, Alzheimer’s disease
DOI / ID Number: 10.25959/100.00031636
Copyright Information:

Copyright 2019 the author

Additional Information:

A published article is located in the appendices: Hanson, K., Tian, N., Vickers, J., King, A., 2018. The HDAC6 inhibitor
trichostatin A acetylates microtubules and protects axons from excitotoxin-induced degeneration in a compartmented culture model, Frontiers in neuroscience, 12, 872. Copyright © 2018 Hanson, Tian, Vickers and King. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution o reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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