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

Nortley, R.; Mishra, A.; Jaunmuktane, Z.; Kyrargyri, V.; Madry, C.; Gong, H.; Richard-Loendt, A.; Brandner, S.; Sethi, H.; Attwell, D.

doi:10.1101/357095

bioRxiv · 10.1101/357095

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

Nortley, R.·Mishra, A.·Jaunmuktane, Z.·Kyrargyri, V.·Madry, C.·Gong, H.·Richard-Loendt, A.·Brandner, S.·Sethi, H.·Attwell, D.

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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.

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Nortley, R., Mishra, A., Jaunmuktane, Z., Kyrargyri, V., Madry, C., Gong, H., Richard-Loendt, A., Brandner, S., Sethi, H., Attwell, D.. 2018-06-27. Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signalling to pericytes. https://doi.org/10.1101/357095

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