Dementia is now the leading cause of death in the UK. Most cases are caused by Alzheimer’s disease (AD), vascular dementia (VaD), or a combination of both. Both AD and VaD are associated with reduced cerebral blood flow, which is thought to contribute to disease progression. Therefore, understanding the mechanisms that regulate cerebral blood flow has become an exciting therapeutic opportunity.

The volume of blood the brain receives is in part determined by the arterial diameter of the small arteries and arteriole that run along the surface of the brain. Intraluminal pressure drives vascular smooth muscle depolarisations which drives voltage gated Ca²⁺ channel activity, and therefore vasoconstriction. To prevent over-constriction, this depolarisation is buffered by the activation of large conductance Ca²⁺ activated K⁺ (BK) channels ensuring correct cerebral perfusion.

We have found in mouse model of Alzheimer’s disease (APP23) that there is a reduction in BK channel activation, which is also present in a mouse model of hypertension induced vascular dementia (BPH/2). Although both models showed impaired BK channel activation, this is via different mechanisms. BK channels are activated by high amplitude spatially and temporally restricted events know as Ca²⁺ sparks. In AD, there is a reduction in Ca²⁺ spark frequency which impairs BK channel function, whereas in VaD this is a physical separation of Ca²⁺ sparks and BK channels.

Because these distinct mechanisms require different strategies to restore normal function and cerebral blood flow, this talk will outline the current approaches we are pursuing.