Abstract

Vascular compromise occurs early in Alzheimers disease (AD) and other dementias1-3. Amyloid {beta} (A{beta}) reduces cerebral blood flow4-6 and, as most of the cerebral vasculature resistance is in capillaries7, A{beta} might mainly act on contractile pericytes on capillary walls8-10. Employing human tissue to establish disease-relevance, and rodent experiments to define mechanism, we now show that A{beta} constricts brain capillaries at pericyte locations in human subjects with cognitive decline. Applying soluble A{beta}1-42 oligomers to live human cortical tissue constricted capillaries. Using rat cortical slices, this was shown to reflect A{beta} evoking capillary pericyte contraction, with an EC50 of 4.7 nM, via the generation of reactive oxygen species and activation of endothelin ET-A receptors. In freshly-fixed diagnostic biopsies from human patients investigated for cognitive decline, mean capillary diameters were less in subjects showing A{beta} deposition than in subjects without A{beta} deposition. For patients with A{beta} deposition, the capillary diameter was 31% less at pericyte somata than away from somata, predicting a halving of blood flow. Constriction of capillaries by A{beta} will contribute to the energy lack1-3 occurring in AD, which promotes further A{beta} generation11,12. This mechanism reconciles the amyloid hypothesis13-15 with the earliest events in AD being vascular1.