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The cells of the oligodendrocyte lineage are differentially altered by tau accumulation and amyloidosis

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Ferreira, SCA ORCID: 0000-0002-0401-0615 2020 , 'The cells of the oligodendrocyte lineage are differentially altered by tau accumulation and amyloidosis', PhD thesis, University of Tasmania.

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Abstract

Oligodendrocytes produce and wrap an insulating, fatty substance called myelin around axons to increase the conduction velocity of action potentials along these axons and to provide them with critical metabolic support. Highly myelinated white matter regions are amongst the first to be damaged in Alzheimer’s disease (AD), and early oligodendrocyte damage has been detected in transgenic mice carrying human genetic variants associated with the development of AD. In diseases such as multiple sclerosis, immature brain cells called oligodendrocyte progenitor cells (OPCs) proliferate and differentiate into myelinating oligodendrocytes in an attempt to replace oligodendrocytes lost to the disease, restore action potential conduction speed and protect neurons from further damage. However, OPC fate in the early stages of ADlike pathology is unknown.
In this thesis, I have shown that the cells of the oligodendrocyte lineage respond differently to hyperphosphorylated microtubule-associated protein tau (tau) (Chapter 3) and amyloidosis (Chapter 4), two major pathological features of AD, respectively recapitulated in transgenic mice by the overexpression in neurons of a human genetic variant of microtubule-associated protein tau (MAPT) or the amyloid precursor protein (APP). Overexpression of MAPT in neurons indirectly increased new oligodendrocyte addition throughout the brain; however, this was not associated with a change in total oligodendrocyte number, proportion of myelinated axons and myelin thickness in MAPT mice compared to WT (Chapter 3). The OPC response to glutamate and GABA was unchanged in pre-symptomatic MAPT mice; however, OPC responded more robustly to GABA in early amyloid pathology. By overexpressing APP in neurons and oligodendrocytes throughout life, developmental myelin thickness was increased, but amyloid plaque formation was also coincident with an increase in oligodendrogenesis between 5 and 6 months of age in APP mice (Chapter 4). Together, this thesis suggests that oligodendrocyte turnover is an early feature of both tau and amyloid pathology, while myelin remodelling only occurs in amyloid pathology, which may result from neurotransmitter or excitatory-inhibitory signalling imbalance within the neuronal network.
My data suggest that OPCs and oligodendrocytes are affected by both tauopathy and amyloidosis, which are critical aspects of pathology in people diagnosed with AD. More specifically, my data suggest that oligodendrocytes are particularly susceptible to undergo cell death in response to these pathological insults. The lost oligodendrocytes are replaced by OPCs early on, suggesting that early interventions that promote oligodendrocyte survival and oligodendrogenesis could be very beneficial for preserving neural circuit function in people with AD, and slowing neurodegeneration in other tauopathies.

Item Type: Thesis - PhD
Authors/Creators:Ferreira, SCA
Keywords: oligodendrocyte precursor cell, oligodendrocyte, myelin, microtubule-associated protein tau, amyloid, tauopathy, Alzheimer's disease, dementia
DOI / ID Number: 10.25959/100.00034892
Copyright Information:

Copyright 2019 the author

Additional Information:

Chapter 3 appears to be the equivalent of a pre-print version of an article published as: Ferreira, S., Pitman, K. A., Summers, B. S., Wang, S., Young, K. M., Cullen, C. L., 2020. Oligodendrogenesis increases in hippocampal grey and white matter prior to locomotor or memory impairment in an adult mouse model of tauopathy, European journal of neuroscience, 00: 1– 23. © 2020 The Authors. European journal of neuroscience published by Federation of European Neuroscience Societies and John Wiley. It is an open access article under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) License, (https://creativecommons.org/licenses/by/4.0/) which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Chapter 4 appears to be the equivalent of a pre-print version of an article published as: Ferreira, S., Pitman, K. A., Wang, S., Summers, B. S., Young, K. M., Cullen, C. L., 2020. Amyloidosis is associated with thicker myelin and increased oligodendrogenesis in the adult mouse brain, European journal of neuroscience, 98(10) 1905-1932 © 2020 The Authors. European journal of neuroscience published by Federation of European Neuroscience Societies and John Wiley. It is an open access article under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) License, (https://creativecommons.org/licenses/by/4.0/) which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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