Alzheimer’s disease (AD) is a neurodegenerative disease; but there is a growing recognition about the vascular dysfunction in the pathophysiology of AD. These observations propose structural and functional loss in microvasculature can be involved in the initial progression of AD. However, early neurovascular deficits in AD are still lacking a thorough understanding. Here, we are studying early cerebrovascular dysfunction in AD by using 5xFAD mouse model (age: 3-months); a familial model of AD. We hypothesized that impairment in Electro-Calcium coupling (a neurovascular coupling mechanism) leads to reduction in the cerebral blood flow and these changes precede the cognitive decline in 5xFAD mice. We combined in-vivo imaging approaches ranging from arterial spin labelling (ASL) MRI, functional ultrasound (fUS), multi-photon and wide-field microscopy with ion channel recordings and behavioral testing in this evaluation. The resting cortical perfusion measured with ASL-MRI showed no significant difference between age-matched controls and 5xFAD mice. However, there was a significant reduction in whisker stimulation induced functional hyperemia in 5xFAD mice compared to the controls; measured using fUS. Next, we evaluated mechanisms involved in reduced functional hyperemia by studying cortical neuronal and endothelial Ca 2+ activity by in-vivo wide-field and multiphoton microscopy imaging respectively. The neuronal Ca 2+ response was similar between controls and 5xFAD mice, however capillary endothelial cells (cECs) Ca 2+ activity was significantly lower in 5xFAD mice. Moreover, inward rectifying K + (Kir2.1) channels blocker Barium (100 µM) caused a significant inhibition in cECs Ca 2+ activity in the control, but not in 5xFAD mice suggesting impairment in Kir2.1 channel functions mediates reduction in Ca 2+ activity (i.e. Electro-Calcium coupling). cECs Kir2.1 current density in 5xFAD mice were lower than controls, further confirming impairment in Kir2.1 channel functions. Lastly, we used a battery of behavioral tests (including Y-maze and novel object recognition) to evaluate spatial learning and memory, where a gradual decline in the cognitive functions was observed in 5xFAD mice, but it was not significantly different than controls. In summary, early vascular functional deficits are contributing to reduced cerebral blood flow in 5xFAD mice, and these changes may lead to neuronal dysfunction and cognitive impairment.
Kwon et al. (Thu,) studied this question.