Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signalling to pericytes

Vascular compromise occurs early in Alzheimer’s disease (AD) and other dementias1–3. Amyloid β (Aβ) reduces cerebral blood flow4–6 and, as most of the cerebral vasculature resistance is in capillaries7, Aβ 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 Aβ constricts brain capillaries at pericyte locations in human subjects with cognitive decline. Applying soluble Aβ1-42 oligomers to live human cortical tissue constricted capillaries. Using rat cortical slices, this was shown to reflect Aβ 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 Aβ deposition than in subjects without Aβ deposition. For patients with Aβ deposition, the capillary diameter was 31% less at pericyte somata than away from somata, predicting a halving of blood flow. Constriction of capillaries by Aβ will contribute to the energy lack1–3 occurring in AD, which promotes further Aβ generation11,12. This mechanism reconciles the amyloid hypothesis13–15 with the earliest events in AD being vascular1.