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Cerebral small vessel disease (SVD) is a major cause of age-related cognitive impairment and dementia. The pathophysiology of SVD is not well understood and is hampered by a limited range of relevant animal models. Here, we describe gliovascular alterations and cognitive deficits in a mouse model of sustained cerebral hypoperfusion with features of SVD (microinfarcts, hemorrhage, white matter disruption) induced by bilateral common carotid stenosis. Multiple features of SVD were determined on T2-weighted and diffusion-tensor magnetic resonance imaging scans and confirmed by pathologic assessment. These features, which were absent in sham controls, included multiple T2-hyperintense infarcts and T2-hypointense hemosiderin-like regions in subcortical nuclei plus increased cerebral atrophy compared with controls. Fractional anisotropy was also significantly reduced in several white matter structures including the corpus callosum. Investigation of gliovascular changes revealed a marked increase in microvessel diameter, vascular wall disruption, fibrinoid necrosis, hemorrhage, and blood–brain barrier alterations. Widespread reactive gliosis, including displacement of the astrocytic water channel, aquaporin 4, was observed. Hypoperfused mice also demonstrated deficits in spatial working and reference memory tasks. Overall, gliovascular disruption is a prominent feature of this mouse, which could provide a useful model for early-phase testing of potential SVD treatment strategies.

Myelinated axons have a distinct protein architecture which is essential for action potential propagation, neuronal communication and maintaining cognitive function. Damage to myelinated axons, associated with cerebral hypoperfusion, is suggested to contribute to age-related cognitive decline. We sought to determine whether there are selective and early alterations in the protein architecture of myelinated axons in response to cerebral hypoperfusion. Using a mouse model of hypoperfusion we assessed changes in proteins, by confocal laser scanning microscopy, critical to the maintenance of the paranodes (contactin-associated protein (CASPR); Neurofascin155 (Nfasc155)), the nodes of Ranvier (voltage-gated sodium channels (Nav1.6), Neurofascin186 (Nfasc186) and AnkyrinG), axon-glial integrity (myelin-associated glycoprotein (MAG)), axon (SMI312) and myelin (myelin basic protein (MBP)). As early as 3 days after hypoperfusion, the paranodal septate-like junctions were damaged. This was marked by a progressive reduction of paranodal Neurofascin signal and a loss of septate-like junctions confirmed by electron microscopy. Concurrent with paranodal disruption there was a significant increase in nodal length, identified by Nav1.6 staining, with hypoperfusion. In contrast, the nodal anchoring proteins AnkyrinG and Nfasc186 were unchanged and there were no changes in axonal and myelin integrity with hypoperfusion. Disruption of axon-glial integrity was also determined after hypoperfusion by changes in the spatial distribution of MAG staining. These nodal/paranodal changes were more pronounced after one month of hypoperfusion. A microarray analysis of white matter enriched samples of sham as compared with hypoperfused mice indicated that there were significant alterations in 129 genes (p