Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.802268
Title: Investigating the role of TREM2 and neuroinflammation in an experimental model of chronic cerebral hypoperfusion
Author: Szymkowiak, Stefan Robert
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2020
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Abstract:
Chronic cerebral hypoperfusion resulting from cerebrovascular disease is associated with the development of white matter damage, cognitive impairment and dementia. Although incompletely understood, recent studies suggest neuroinflammation is a key mechanism driving vascular pathology, white matter damage and cognitive decline. Neuroinflammation is observed in various neurological conditions and is implicated in both the initiation and progression of dementia. Mutations in the microglial immunoreceptor triggering receptor expressed on myeloid cells 2 (TREM2) increase susceptibility to neurodegenerative conditions and dementia providing key evidence for the role of microglial dysfunction in dementia pathogenesis. Precisely how TREM2 dysfunction contributes to neurodegeneration and dementia remains to be established, particularly in relation to cerebrovascular causes of degeneration. To investigate the contribution of TREM2 to cerebrovascular-mediated white matter damage, the bilateral common carotid artery stenosis (BCAS) model of chronic cerebral hypoperfusion was implemented in wild type (WT) and TREM2-/- C57BL/6Ntac mice. Initial studies demonstrated 0.18 mm internal diameter microcoils failed to induce sufficient white matter pathology or neuroinflammatory changes in WT C57BL/6Ntac mice. However, implementation of microcoils with smaller internal diameters (0.16 mm) precipitated robust myelin damage associated with neuroinflammation. In the absence of TREM2 expression, myelin damage was exacerbated and microglial responses to BCAS were blunted as assessed by immunohistochemistry and flow cytometric analysis. Collectively, the data presented in this thesis suggest TREM2 plays a key role in regulating microglial responses to chronic cerebral hypoperfusion. Given that TREM2 deficiency exacerbated myelin damage, it appears TREM2 confers protection to cerebrovascular dysfunction. However, the precise mechanisms remain unclear. Furthermore, the effects of TREM2 deficiency on white matter function and cognition remain unknown. Future studies investigating the impact of chronic cerebral hypoperfusion on the microglial transcriptome will advance our understanding of microglial function and neuroinflammation in the context of vascular cognitive impairment (VCI) and dementia. Such studies may reveal novel TREM2 regulated pathways that attenuate neurodegenerative processes and ameliorate cognitive impairment.
Supervisor: McColl, Barry ; Horsburgh, Karen Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.802268  DOI:
Keywords: vascular dementia ; neuroinflammation ; animal models ; microglia ; TREM2 ; cerebral hypoperfusion
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