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Gliovascular disruption and cognitive deficits in a mouse model with features of small vessel disease

Lookup NU author(s): Professor Raj KalariaORCiD

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Abstract

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.

Publication metadata

Author(s): Holland PR, Searcy JL, Salvadores N, Scullion G, Chen GQ, Lawson G, Scott F, Bastin ME, Ihara M, Kalaria R, Wood ER, Smith C, Wardlaw JM, Horsburgh K

Publication type: Article

Publication status: Published

Journal: Journal of Cerebral Blood Flow & Metabolism

Year: 2015

Volume: 35

Issue: 6

Pages: 1005-1014

Print publication date: 01/06/2015

Online publication date: 01/06/2015

Acceptance date: 13/01/2015

ISSN (print): 0271-678X

ISSN (electronic): 1559-7016

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/jcbfm.2015.12

DOI: 10.1038/jcbfm.2015.12

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