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Science. 2019 Jun 20. pii: eaav9518. doi: 10.1126/science.aav9518. [Epub ahead of print]

Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes.

Author information

1
Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK.
2
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR 97239, USA.
3
Division of Neuropathology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
4
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK.
5
Molecular Physiology, CIPPM, University of Saarland, D-66421 Homburg, Germany.
6
Laboratory for Proteolytic Neuroscience, RIKEN Centre for Brain Science, Wako, Saitama 351-0198, Japan.
7
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK.
8
Division of Neurosurgery, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK.
9
Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK. d.attwell@ucl.ac.uk.

Abstract

Cerebral blood flow is reduced early in Alzheimer's disease (AD). Because most of the vascular resistance within the brain is in capillaries, this could reflect dysfunction of contractile pericytes on capillary walls. Here we used live and rapidly-fixed biopsied human tissue to establish disease-relevance, and rodent experiments to define mechanism. We found that, in humans with cognitive decline, amyloid β (Aβ) constricts brain capillaries at pericyte locations. This was caused by Aβ generating reactive oxygen species, which evoked the release of endothelin-1 (ET) that activated pericyte ETA receptors. Capillary, but not arteriole, constriction also occurred in vivo in a mouse model of AD. Thus, inhibiting the capillary constriction caused by Aβ could potentially reduce energy lack and neurodegeneration in AD.

PMID:
31221773
DOI:
10.1126/science.aav9518

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