- Title
- Impaired processes dynamics of activated microglia in areas of secondary neurodegeneration after ischemic stroke in mice
- Creator
- Kluge, Murielle Gabriela
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2018
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Stroke is the leading cause of disability worldwide and yet chronic treatment options are limited to the improvement of motor function impairment. Clinical and pre-clinical research is therefore focusing on a better understanding of the processes contributing and influencing mechanisms of neurological damage and recovery in later stages after stroke. One of the most common neurological processes in the chronic phases of stroke is the development of secondary neurodegeneration (SND). SND develops in brain regions remote but synaptically connected to the primary infarct site and is defined as the progressive neuronal loss together with an accumulation of protein aggregates and glial activation. As SND develops after the primary infarct and progresses over a much longer period (weeks to years) it provides a promising interventional target for chronic stroke treatment. This thesis is investigating the basic mechanisms involved in SND, in particular the actions and functions of the resident immune cells of the brain, microglia cells. Microglia activation is a hallmark of SND, however their functional contribution and involvement to SND has received little attention. I was particularly interested in microglial process movement and the functional consequences at sites of SND. A photothrombotic stroke model in mice, in combination with acute slice based, multi-photon and confocal imaging, was used to visualise live microglia movement in the brain after stroke. This thesis identifies and provides an in depth characterisation of a novel microglia behaviour specific to sites of SND. Microglial at sites of SND lose their ability to perform process extension to local damage, a highly conserved form of microglia movement. Further spatiotemporal analysis of microglia showed that microglia process response is not impaired at the infarct site but that the loss of process movement correlates to microglia activation and neuronal loss only in the thalamus, a major site of post-stroke SND. Impaired process extension towards a site of damage appears not to be a sign of general functional paralysis as microglia maintain phagocytic functions and general process movement. The assessment of protein expression profiles of microglia revealed alterations of the purinergic P₂Y₁₂ receptor, the main mediator of process extension. These alterations where observed particularly in the early stages of non-responsiveness, suggesting a disruption of the P₂Y₁₂R pathway. Additionally, this thesis used a protein-focused approach to compare the effect of age on the development of SND. Results indicate that age exacerbates neuronal damage and protein aggregation in SND but presumably not via glial interactions. This provides evidence that the results obtained in younger animals, concerning microglia alterations at sites of SND, are likely translatable across ages. In conclusion, this thesis provides novel observations and insights into microglia functions at sites of SND, supports microglia process movement as potential modulator of SND and provides fruitful directions for future research.
- Subject
- microglia; stroke; secondary neurodegeneration; multi-photon imaging; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1390615
- Identifier
- uon:33096
- Rights
- Copyright 2018 Murielle Gabriela Kluge
- Language
- eng
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 16 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 385 KB | Adobe Acrobat PDF | View Details Download |