Abstract
Chronic cerebral hypoperfusion is a key mechanism associated with white matter disruption in cerebral vascular disease and dementia. In a mouse model relevant to studying cerebral vascular disease, we have previously shown that cerebral hypoperfusion disrupts axon-glial integrity and the distribution of key paranodal and internodal proteins in subcortical myelinated axons. This disruption of myelinated axons is accompanied by increased microglia and cognitive decline. The aim of the present study was to investigate whether hypoperfusion impairs the functional integrity of white matter, its relation with axon-glial integrity and microglial number, and whether by targeting microglia these effects can be improved. We show that in response to increasing durations of hypoperfusion, the conduction velocity of myelinated fibres in the corpus callosum is progressively reduced and that paranodal and internodal axon-glial integrity is disrupted. The number of microglial cells increases in response to hypoperfusion and correlates with disrupted paranodal and internodal integrity and reduced conduction velocities. Further minocycline, a proposed anti-inflammatory and microglia inhibitor, restores white matter function related to a reduction in the number of microglia. The study suggests that microglial activation contributes to the structural and functional alterations of myelinated axons induced by cerebral hypoperfusion and that dampening microglia numbers/proliferation should be further investigated as potential therapeutic benefit in cerebral vascular disease.
Highlights
Disease (Barker, Wellington, Esiri, & Love, 2013; Ihara et al, 2010) with evidence that this may be related to reduced white matter perfusion
Perfusion elicits diffuse damage to myelinated axons accompanied by a pronounced pro-inflammatory response and impaired spatial working memory. (Coltman et al, 2011; Holland et al, 2011, 2015; McQueen, Reimer, Holland, & Horsburgh, 2014; Reimer et al, 2011; Shibata, Ohtani, Ihara, & Tomimoto, 2004) hypoperfusion leads to the disruption of key paranodal and internodal proteins which are essential for the stability of the axon-glial connection (Reimer et al, 2011)
Previous studies, including our own, indicated that disruption of white matter structure induced by chronic cerebral hypoperfusion (Coltman et al, 2011; Holland et al, 2011; Reimer et al, 2011; Shibata et al, 2004) is closely linked with a robust increase in microglia number
Summary
Disease (Barker, Wellington, Esiri, & Love, 2013; Ihara et al, 2010) with evidence that this may be related to reduced white matter perfusion. Increased numbers of activated microglia have been linked to axon-glial disruption in an experimental model of multiple sclerosis (Howell et al, 2010) It is not clear, whether these changes in microglia number or phenotype contribute to, or are consequence of, the damage to myelinated axons. The aim of the present study was to investigate whether, in response to increased durations of hypoperfusion, the functional integrity of white matter is impaired and related to axon-glial integrity and microglia numbers/proliferation. Second to this we tested the potential protective effect of minocycline on white matter function and microglia numbers/proliferation
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