Neural circuit mechanisms underlying aberrantly prolonged functional hyperemia in young Alzheimer's disease mice.

Neurovascular defects are one of the most common alterations in Alzheimer's disease (AD) pathogenesis, but whether these deficits develop before the onset of amyloid beta (Aβ) accumulation remains to be determined. Using in vivo optical imaging in freely moving mice, we explored activity-induced hippocampal microvascular blood flow dynamics in App knock-in and J20 mouse models of AD at early stages of disease progression. We found that prior to the onset of Aβ accumulation, there was a pathologically elevated blood flow response to context exploration, termed functional hyperemia. After the onset of Aβ accumulation, this context exploration-induced hyperemia declined rapidly relative to that in control mice. Using in vivo electrophysiology recordings to explore the neural circuit mechanism underlying this blood flow alteration, we found that hippocampal interneurons before the onset of Aβ accumulation were hyperactive during context exploration. Chemogenetic tests suggest that hyperactive activation of inhibitory neurons accounted for the elevated functional hyperemia. The suppression of nitric oxide (NO) produced from hippocampal interneurons in young AD mice decreased the accumulation of Aβ. Together, these findings reveal that neurovascular coupling is aberrantly elevated before Aβ deposition, and this hyperactive functional hyperemia declines rapidly upon Aβ accumulation.