The effect of ApoE4 on neurovascular coupling in the visual cortex

Neurovascular coupling (NVC) is the process whereby the brain increases local blood supply in response to neuronal activity, providing neurons with energy. Disruptions to NVC have been implicated in Alzheimer's disease (AD), so a better understanding of how NVC goes wrong, and when, is imperative for better understanding the disease and assisting in the identification of therapeutic targets. The main genetic risk factor for developing AD, expression of Apolipoprotein e4 (APOE4), is associated with vascular deficits, including pericyte damage and impaired cerebral blood ow. I tested whether expression of APOE4 affected NVC, by studying neuronal activity and vascular responses in visual cortex. To investigate this, mice with humanised APOE4 or APOE3 were crossed with mice expressing a genetically-encoded calcium indicator or with labelled pericytes. Mice were implanted with a cranial window over visual cortex and neuronal and vascular activity was recorded using two-photon microscopy. Baseline and stimulus evoked measurements were taken to determine the effect of ApoE4 on basal energy balance and on the ability of the brain to deliver adequate energy to neurons. Results suggest that there were some baseline alterations in APOE4 mice that may result in a lower energy supply. Compounding this, I found there to be a mismatch in energy supply and demand during sensory stimulation, where neuronal demand was greater, but blood supply was less reliable in APOE4 mice. Together these data suggest that there could be an energy deficit in APOE4 carriers. In vivo studies investigating the role of ApoE4 in NVC are few and the study of individual vessels and neurons across different age points, as done in this body of work, is a novel and unique approach. By better understanding how ApoE4 modulates neurovascular function, we can better understand its role in AD pathology and possibly identify therapeutic targets in the future.