Abstract
Vascular cognitive impairment is the second most common form of dementia. The pathogenic pathways leading to vascular cognitive impairment remain unclear but clinical and experimental data have shown that chronic reactive astrogliosis occurs within white matter lesions, indicating that a sustained pro-inflammatory environment affecting the white matter may contribute towards disease progression. To model vascular cognitive impairment, we induced prolonged mild cerebral hypoperfusion in mice by bilateral common carotid artery stenosis. This chronic hypoperfusion resulted in reactive gliosis of astrocytes and microglia within white matter tracts, demyelination and axonal degeneration, consecutive spatial memory deficits, and loss of white matter integrity, as measured by ultra high-field magnetic resonance diffusion tensor imaging. White matter astrogliosis was accompanied by activation of the pro-inflammatory transcription factor nuclear factor (NF)-kB in reactive astrocytes. Using mice expressing a dominant negative inhibitor of NF-kB under the control of the astrocyte-specific glial fibrillary acid protein (GFAP) promoter (GFAP-IkBα-dn), we found that transgenic inhibition of astroglial NF-kB signaling ameliorated gliosis and axonal loss, maintained white matter structural integrity, and preserved memory function. Collectively, our results imply that pro-inflammatory changes in white matter astrocytes may represent an important detrimental component in the pathogenesis of vascular cognitive impairment, and that targeting these pathways may lead to novel therapeutic strategies.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0350-3) contains supplementary material, which is available to authorized users.
Highlights
Vascular cognitive impairment (VCI) is a common neurodegenerative disease characterised by impaired cognitive function attributable to cerebrovascular pathology [1]
We demonstrate that reactive astrogliosis induces activation of the pro-inflammatory nuclear factor (NF)-kB pathway in astrocytes, and that transgenic inhibition of this pathway confers protection against axonal loss, helps to promote white matter integrity, and preserves cognitive function
Demyelination, axonal loss and memory deficits in a mouse model of VCI We modified a model of bilateral common carotid artery stenosis (BCAS) [13] by placing microcoils around both common carotid arteries to induce chronic cerebral hypoperfusion in mice (Fig. 1a)
Summary
Vascular cognitive impairment (VCI) is a common neurodegenerative disease characterised by impaired cognitive function attributable to cerebrovascular pathology [1]. In its pure form, VCI is the second most common form of dementia and represents an important co-factor for the development of Alzheimer’s disease and other neurodegenerative disorders [2]. VCI is characterised by demyelination and axonal loss within white matter tracts [3], which has traditionally been attributed to the direct effects of chronic oxygen deprivation. Saggu et al Acta Neuropathologica Communications (2016) 4:76 cascades mediated by reactive astrocytes in chronic cerebral hypoperfusion and VCI remain poorly understood. We demonstrate that reactive astrogliosis induces activation of the pro-inflammatory nuclear factor (NF)-kB pathway in astrocytes, and that transgenic inhibition of this pathway confers protection against axonal loss, helps to promote white matter integrity, and preserves cognitive function
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