Dysregulated microvascular reactivity in hippocampus and cortex in CVN Alzheimer’s disease mouse model

Microvascular reactivity in acute cortical and hippocampal brain slices and hippocampal synaptic- evoked cerebral blood flow (CBF) in vivo were analyzed in a mouse model of Alzheimer's disease (AD, CVN). Microvessels underwent initial vasoconstriction (2 µM noradrenaline) then treatment with either 0.5 mM glutamate or 100 µM NMDA. In acute brain slices from young mice (<20 weeks) the glutamate and NMDA treatment led to dilation of capillaries in cortex and hippocampus, but not in aged CVN mice (>30 weeks, with AD pathology). Furthermore, 1 mM adenosine restored pre-constricted capillaries to control levels in WT but not in aged CVN brain slices. Stimulation of endothelial ET-1 receptors (10 nM ET-1) showed enhanced vasoconstriction in hippocampal capillaries of aged CVN slices, but blockade of both ET-1A/1B receptors did not alter basal capillary tone in aged CVN slices. Stimulation-evoked hippocampal CBF in vivo was significantly reduced in aged CVN mice. These results provide evidence for a progressive, complex age- and AD pathology-related impairment of vascular reactivity and vasodilation in the CVN model. The dysregulation of NVC function and reduced functional hyperemia in aged CVN AD mice may underscore dynamic hypoperfusion and metabolic insufficiency, which could accelerate progression in AD.