Although the generation of amyloid beta oligomers and plaques, and of hyperphosphorylated tau, are hallmarks of Alzheimer's disease (AD), it has been shown that an earlier change in AD is a decrease of cerebral blood flow (CBF) by ~50% in affected brain areas. Cerebral blood flow can also decrease in vascular dementia.

 

By imaging capillary diameter in neuropathological biopsy sections from the right prefrontal cortex of humans developing AD we previously showed that capillaries in humans with AD are constricted as a result of pericyte contraction (Nortley et al., 2019). A similar pericyte-mediated constriction of capillaries in vivo was seen using 2-photon imaging through a cranial window in anaesthetised AD mice (APP^NL-G-F mice) expressing dsRed in pericytes controlled by the NG2 promoter. In the mice we also showed that there was no constriction of arterioles or venules, and that the capillary constriction leads to a stalling of neutrophils near pericyte locations and to tissue hypoxia.

 

In rodent brain slices we found that applying exogenous oligomerised amyloid beta (EC50~6 nM) led to a pericyte-mediated constriction  of capillaries, that was generated by endothelin-1 (ET) release and activation of ET_A receptors (Nortley et al., 2019). This reflected reactive oxygen species generation, since it was reduced by NOX4 and NOX2 blockers (Nortley et al., 2019). ET-evoked pericyte contraction is amplified by a rise of [Ca²⁺]_I activating TMEM16A chloride channels, which generate a depolarisation that activates voltage-gated Ca²⁺ channels (Korte et al., 2022).

 

To attempt to use a re-purposed drug to reverse the capillary constriction in AD, we employed the voltage-gated calcium channel blocker nimodipine, which is licensed for human use in sub-arachnoid haemorrhage. Giving nimodipine, either intravenously, or in the drinking water from 1.5 to 4 months of age, led to a relaxation of pericytes and arteriolar smooth muscle cells, an increase of cerebral blood flow, a block of the stalling of neutrophils in capillaries, and a partial reversal of the tissue hypoxia.

 

Other possible therapeutic targets for reversing or preventing a decrease of cerebral blood flow in AD or in some types of vascular dementia would include the mechanisms leading to endothelin release in AD, ET_A receptors, TMEM16A channels, and the concentration of cyclic nucleotides in contractile mural cells where a rise of cGMP and cAMP concentration (for example in response to a guanylate cyclase receptor agonist: Nortley et al., 2019) leads to vasorelaxation. Agents that increase cerebral blood flow are likely to be useful as adjunct therapies with other dementia-targeting drugs.