On 19 July, Dr Ross Nortley and colleagues published a paper in Science showing how accumulating amyloid beta (Aβ) causes neurovascular pericytes to contract, leading to brain capillary constriction and vascular dysfunction in Alzheimer’s disease (AD).
Decreased cerebral blood flow is one of the earliest biomarkers of AD, a measure of the vascular dysfunction that underlies AD development. Recent studies on vascular dysfunction in AD have shone a spotlight on brain capillaries, blood vessels so tiny that red blood cells flow down them in single file. Despite their tiny size, brain capillaries fulfil very important functions in the brain, forming the blood-brain barrier and helping to regulate cerebral blood pressure. Narrowing of the capillaries (also known as capillary constriction) has been observed in the brains of people with AD and is correlated with cognitive decline. In this elegant study, Dr Nortley and colleagues hypothesised that pericytes, specialised vascular cells that wrap around brain capillaries, may contribute to capillary constriction in AD.
First, the researchers used surplus brain samples from patients undergoing brain surgery to look at the function of pericytes in brain capillaries. Using advanced tissue imaging techniques, they showed that application of Aβ to live capillaries induced an acute constriction of these blood vessels. Validating these results in animal models of AD, they found that capillary constriction was particularly marked in the vicinity of pericytes, with the degree of constriction correlated to the quantity of Aβ applied. Looking for culprit molecules that might cause pericytes to contract and constrict capillaries, the researchers focused on the NADPH oxidase (NOX) family of proteins. NOX proteins are enzymes that produce free radicals such as superoxide, damaging compounds that are known to promote hypertension through their pro-contractile actions. Using their imaging approach, Dr Nortley and colleagues discovered that Aβ actives NOX4 in pericytes, kicking off a cascade that starts with free radical generation and pericyte contraction, and culminates in capillary constriction. Crucially, blockade of NOX4 using a drug called GKT137831 reduced the capillary constriction evoked by Aβ; application of c-natriuretic peptide (a peptide that can reduce pericyte contractility) had similar effects, highlighting the central role of pericytes in AD-associated vascular dysfunction.
https://science.sciencemag.org/content/365/6450/eaav9518.full