High cholesterol triggers white matter alterations and cognitive deficits in a mouse model of cerebrovascular disease: benefits of simvastatin

Transgenic mice overexpressing transforming growth factor-beta 1 (TGF mice) display impaired cerebrovascular reactivity, cerebral hypoperfusion and neurovascular uncoupling, but no overt cognitive deficits until old age. Cardiovascular diseases are a major risk factor for vascular cognitive impairment and dementia (VCID). We investigated the impact of a high cholesterol diet (HCD) on cerebrovascular and cognitive function in adult (6 months) and aged (12 months) TGF mice, together with the potential benefit of simvastatin (SV), an anti-cholesterol drug with pleiotropic effects, in adult mice. HCD increased blood, but not brain, cholesterol levels in treated mice, which SV did not reduce. In WT mice, HCD induced small, albeit significant, impairment in endothelium-dependent dilatory function. In TGF mice, HCD worsened the established brain vessel dilatory dysfunction in an age-dependent manner and increased the number of string vessels in the white matter (WM), alterations respectively normalized and significantly countered by SV. HCD triggered cognitive decline only in TGF mice at both ages, a deficit prevented by SV. Concurrently, HCD upregulated galectin-3 immunoreactivity in WM microglial cells, a response significantly reduced in SV-treated TGF mice. Grey matter astrogliosis and microgliosis were not affected by HCD or SV. In the subventricular zone of adult HCD-treated TGF mice, SV promoted oligogenesis and migration of oligodendrocyte progenitor cells. The results demonstrate that an underlying cerebrovascular pathology increases vulnerability to cognitive failure when combined to another risk factor for dementia, and that WM alterations are associated with this loss of function. The results further indicate that myelin repair mechanisms, as triggered by SV, may bear promise in preventing or delaying cognitive decline related to VCID.