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SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein

Nature Neuroscience volume 2, pages 157–161 (1999)Cite this article

Abstract

Peptides derived from proteolytic processing of the β–amyloid precursor protein (APP), including the amyloid–β peptide, are important for the pathogenesis of Alzheimer's dementia. We found that transgenic mice overexpressing APP have a profound and selective impairment in endothelium–dependent regulation of the neocortical microcirculation. Such endothelial dysfunction was not found in transgenic mice expressing both APP and superoxide dismutase–1 (SOD1) or in APP transgenics in which SOD was topically applied to the cerebral cortex. These cerebrovascular effects of peptides derived from APP processing may contribute to the alterations in cerebral blood flow and to neuronal dysfunction in Alzheimer's dementia.

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Figure 1: Effects of endothelium–dependent vasodilators and vasocontrictors on cerebral blood flow in nontransgenic mice (APP-/SOD1-) and in littermates overexpressing APP (APP+/SOD1-), SOD1 (APP-/SOD1+) or both APP and SOD1 (APP+/SOD1+).
Figure 2
Figure 3: Brain Aβ levels in Tg1130H–derived APP+/SOD1- or APP+/SOD1+, and in transgene–positive FVB/N Tg6209 mice.
Figure 4: Electron micrographs of thin sections from parietal cortex of mice.
Figure 5: Effect of topical application of SOD to the cerebral cortex on CBF responses in Tg6209 APP+ and APP- littermates.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (NS34179, NS37853, NS35806 to C.I.; NS33249 to K.K.H; AG10681 to G.A.C.) and the Fraternal Order of Eagles (G.A.C.). We thank G. Perry for the oxidative stress data and Karen MacEwan for editorial assistance.

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Authors and Affiliations

  1. Department of Neurology, University of Minnesota, 420 Delaware Street S.E., Minneapolis, 55455, Minnesota , USA

    Costantino Iadecola, Fangyi Zhang, Kiyoshi Niwa & Karen K. Hsiao

  2. Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, 32224, Florida, USA

    Chris Eckman & Steven Younkin

  3. McLaughlin Research Institute, 1520 23rd Street South,, Great Falls, 59405 , Montana, USA

    Sherry K. Turner & George A. Carlson

  4. Rocky Mountain Laboratory, National Institute of Allergy and Infectious Diseases, 903 South 4th Street, Hamilton, 59840, Montana, USA

    Elizabeth Fischer

  5. Division of Neuropathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore , 21205, Maryland, USA

    David R. Borchelt

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Correspondence to Costantino Iadecola.

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Iadecola, C., Zhang, F., Niwa, K. et al. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat Neurosci 2, 157–161 (1999). https://doi.org/10.1038/5715

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