Spontaneous white matter damage, cognitive decline and neuroinflammation in middle-aged hypertensive rats: an animal model of early-stage cerebral small vessel disease

Abstract

IntroductionCerebral small vessel disease (cSVD) is one of the most prevalent neurological disorders. The progressive remodeling of brain microvessels due to arterial hypertension or other vascular risk factors causes subtle, but constant cognitive decline through to manifest dementia and substantially increases the risk for stroke. Preliminary evidence suggests the contribution of the immune system to disease initiation and progression, but a more detailed understanding is impaired by the unavailability of appropriate animal models. Here, we introduce the spontaneously hypertensive rat (SHR) as a model for early onset cSVD and unveiled substantial immune changes in conjunction with brain abnormalities that resemble clinical findings.ResultsIn contrast to age-matched normotensive Wistar Kyoto (WKY) rats, male SHR exhibited non-spatial memory deficits. Magnetic resonance imaging showed brain atrophy and a reduction of white matter volumes in SHR. Histological analyses confirmed white matter demyelination and unveiled a circumscribed blood brain barrier dysfunction in conjunction with micro- and macrogliosis in deep cortical regions. Flow cytometry and histological analyses further revealed substantial disparities in cerebral CD45high leukocyte counts and distribution patterns between SHR and WKY. SHR showed lower counts of T cells in the choroid plexus and meningeal spaces as well as decreased interleukin-10 levels in the cerebrospinal fluid. On the other hand, both T and NK cells were significantly augmented in the SHR brain microvasculature.ConclusionsOur results indicate that SHR share behavioral and neuropathological characteristics with human cSVD patients and further undergird the relevance of immune responses for the initiation and progression of cSVD.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0169-8) contains supplementary material, which is available to authorized users.

Microglia and Monocyte-Derived Macrophages in Stroke

“…Overexpression of junctional adhesion molecule-1 leads to leukocyte adherence to microvasculature, resulting in hypertension in previously normotensive rats [222]. Hypertension causes activation of astrocytes and microglia and elevates expression of adhesion molecules in endothelial cells [223][224][225]. Microglia activation has been observed in angiotensin-II-induced hypertensive rats and intracerebroventricular administration of minocycline abrogated the angiotensin-II-induced hypertension [226].…”

The neuropathology and cerebrovascular mechanisms of dementia

“…121 Moreover, the immune response was shown to be critical in cerebral small-vessel disease and VaD, displaying increased T-cell production in the microvasculature and decreased IL-10 levels in the CSF. 122 …”

Rat white matter injury model induced by endothelin-1 injection: technical modification and pathological evaluation

“…The global hypoperfusion model based on bilateral carotid artery occlusion, and the cerebral small vessel disease model simulating the pathophysiology of the aging brain and induction of white matter injury are such types of models. However, these models also affect the whole brain (including the gray matter), and the lesions mimic more chronic leukoaraiosis rather than sudden onset focal ischemic white matter infarction (Wakita et al 1994, Kaiser et al 2014. Selective white matter lesions can be induced by stereotactic injection of ouabain, a Na/K ATPase pump inhibitor, as previously reported (Janowski et al 2008, Shichinohe et al 2013, Tan et al 2015).…”