To define the mechanism reducing cerebral blood flow in Alzheimer’s disease (AD).

Normal vascular function is crucial for supplying neurons with energy. Brain blood flow is reduced early in AD causing neurodegeneration. Most of the resistance to cerebral blood flow is in capillaries, and is regulated by pericytes, but the role of pericytes in reducing cerebral blood flow in AD is poorly understood.

Fixed cortical biopsies from patients with dementia of unknown cause were labelled for pericytes and amyloid beta (Aβ) deposition, and capillary diameter was measured as a function of Aβ deposition and of distance from pericyte somata. Live slices from normal human brain tissue, removed to access tumours during operations, were perfused with oligomerised Aβ_1-42 to observe effects on capillaries at pericyte locations. Similar Aβ application experiments were performed on rat brain slices with and without pharmacologic blockers applied. This work has been partly published as DOI:.

Compared to dementia patients without Aβ deposition, patients with Aβ deposition showed an 8.1% reduction in cerebral capillary diameter, which occurred mainly near pericyte somata and is predicted to halve cerebral blood flow.  In live human or rodent brain slices, oligomeric Aβ_1-42 constricted cerebral pericytes with an EC50 of 4.7nM. The Aβ-evoked capillary constriction was reduced by a specific NADPH oxidase (NOX) 4 inhibitor (GKT137831), an iron chelator (deferoxamine) or an endothelin-A receptor blocker (BQ123). The progression of Aβ-evoked vasoconstriction was halted by the application of GKT137831 and BQ123, and was reversed by the vasodilator C-type natriuretic peptide (CNP).

Cerebral blood flow compromise in AD reflects capillary pericyte constriction, which may be triggered by Aβ acting through NOX4, hydroxyl radical and endothelin-1. Therapeutically targeting the Aβ-evoked constriction by blocking NOX4 and endothelin-1, or using CNP, may improve blood flow and cognitive function in AD.