Neural activity dependent regulation of vascular: implications for Alzheimers disease

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ABSTRACT Neurons rely on a continuous supply of oxygen and nutrients from the blood in order to function properly. To meet this need, local blood flow increases immediately following neural activity, a phenomenon known as neurovascular coupling (NVC). NVC involves is mediated by cellular interactions among neurons, astrocytes, mural cells, and endothelial cells (ECs). While NVC has been studied for over a century, there is still much unknown about this complicated process. A more active role for ECs in NVC has recently come to light, and there is likely much more to uncover regarding EC contribution to NVC. As NVC is crucial for proper brain function, NVC dysfunction can lead to cognitive deficits. NVC declines in aging and neurological diseases, with neural activity eliciting a weaker increase in blood flow. However, the mechanisms underlying NVC dysfunction are unclear. Our preliminary data show that neural activity dynamically regulates EC cholesterol synthesis and uptake. We also found that microglial depletion similarly alters EC cholesterol metabolism. As cellular membrane cholesterol content alters the rigidity and cytoskeletal structure of the cell, it may be that dynamic changes in EC cholesterol metabolism allow ECs to biophysically accommodate NVC. Interestingly, disruptions in cholesterol homeostasis are a strong risk factor for AD. We hypothesize that NVC leads to dynamic, activity-dependent changes in EC cholesterol metabolism, with microglia acting as mediators between synapses and ECs. We further hypothesize that EC cholesterol dysregulation occurs with NVC deficits in AD. In this proposal, we will first test the mechanistic link between NVC and EC cholesterol homeostasis. We will then investigate how microglia interact with neural activity in regulating EC cholesterol. Finally, we will assess neural activity-dependent regulation of EC cholesterol dynamics in a mouse model of AD with cerebral amyloid angiopathy. Together, the proposed experiments will advance our mechanistic understanding of the novel finding that neural activity regulates EC cholesterol metabolism. Furthermore, these data will identify whether therapeutic regulation of cholesterol synthesis or efflux specifically in brain ECs could be a successful clinical strategy for preventing NVC deficits in aging and AD.