Single vascular insult exacerbates disease pathology in APPswe Mice.

Abstract

AbstractBackgroundVascular insults, such as microinfarcts play a major role in mixed dementia including Alzheimer’s disease (AD). Neuroimaging from longitudinal studies have shown involvement of white matter hyperintensities due to blood brain barrier (BBB) breakdown. In patients with AD the combined neurotoxic effects of amyloid‐β (Aβ) converge on brain vasculature synergistically leading to neuronal and synaptic dysfunction, which in turn leads to cognitive impairment. In the present study we examined the effect of vascular insult induced by enothelin‐1 (ET‐1, a vasoconstrictor peptide) on Aβ pathology in mouse models of AD. We further studied behavioral deficits during reduced cerebral blood flow changes and structural changes in BBB components.MethodWe injected 2µg/2μl of ET‐1 bilaterally into lateral ventricles APPswe mice carrying point mutation for APP. Behavioral assays were performed to compare associative learning and spatial memory deficits, if any after 30 days of ET‐1 injection. Immunohistochemistry for markers of endothelial cells and pericytes were done to look at the structural changes in BBB. Aβ ELISA and plaque load were tested to understand the effect of vascular insult on AD pathology.ResultVasoconstriction following ET‐1 injection after 30 days leads to memory deficits in AD mice while wildtype mice recovered. There were structural changes in BBB showing decreased expression of endothelial and pericyte marker, however these changes were not observed in wildtype mice. Aβ levels were increased in brain lysates of APPswe mice injected with ET‐1.ConclusionSingle vascular insult was adequate to bring about impairment in learning and memory in APPswe mice and structural changes in BBB, which were not seen in WT type mice indicating that ET‐1 induced cerebral hypoperfusion accelerated AD pathogenesis.