Introduction
Active neurons dilate nearby blood vessels, ensuring sufficient oxygen availability, fuelling this activity. Neurovascular coupling (NVC) mechanisms facilitating this functional hyperaemia may be disrupted early in Alzheimer’s Disease (AD) pathogenesis through direct actions of Beta-Amyloid (Aβ) on neurovasculature and/or induction of chronic neuronal hyperexcitability, impairing the ability of healthy NVC to be sustained. The hippocampus is affected early in AD which may be partly driven by its lower vascularisation and NVC response compared to cortex, making it particularly vulnerable to further NVC disruption. APOE4, the strongest risk allele for sporadic AD, may also confer compromised NVC in carriers, and is an integral link between systemic cardiovascular health and AD.
Aims
In the current study we aim to unpick contributions of Aβ accumulation and APOE genotype to early-AD NVC impairment, comparing the hippocampus to the visual cortex.
Methods
To do this we have employed a novel mouse model combining humanised APOE (3/3 or 4/4) and doxycycline-inducible APPSwe/Ind transgenes, as well as the CaMKII driven GCaMP6f neuronal calcium indicator. By measuring, in vivo, brain blood flow and oxygenation, neuronal activity, and vascular dilatory responses, before and after induction of Aβ expression we aim to untangle the relative impact of low level Aβ on different aspects of neurovascular physiology, and to understand how these changes could feed into gradual neurodegeneration.
Statistical Analyses
Data were analysed using linear mixed models to determine the effects of genotype, time off doxycycline and brain region, with animal ID specified as the random factor (n=7-18 mice per condition).
Ethics
All experimental procedures were approved by the UK Home Office, in accordance with the 1986 Animal (Scientific Procedures) Act, and the University of Sussex animal welfare ethical review board.
Results
Preliminary data suggests that soluble but not aggregated Aβ increases in both cortex hippocampus over 3 months, causing cortical neurons to become hyperexcitable. Over the same timescale, cortical blood flow increases from baseline, possibly to counter this hyperexcitability, but decreases in the hippocampus. However, blood oxygenation decreases in both the cortex and hippocampus, suggesting any increase in blood flow is insufficient to counter increased oxygen consumption by neurons.
Conclusions & Future Directions
Ongoing analyses will interrogate influences of APOE genotype, characterise any effect on hippocampal neurons and cortical and hippocampal NVC.