Research Article

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

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Science  19 Jul 2019:
Vol. 365, Issue 6450, eaav9518
DOI: 10.1126/science.aav9518

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  • RE: Amyloid Beta Oligomers Constrict Capillaraies
    • David Irwin, Associate Director (Retired), Lombardy Comprehensive Cancer Center

    The research reported by Nortley et al., summarized by Arthur Liesz in the July 19 issue of Science points to some intriguing possibilities for the treatment of Alzheimer’s Disease (AD). The key observation in an animal model of AD and in brain tissue slices from AD patients is that capillary constriction caused by the effects of Amyloid Beta plaques on pericytes causes local vascular dysfunction and neurodegeneration. This work raises two key questions for which we probably have data to provide the answers: 1) Do mildly hypertensive patients taking vasodilator drugs have a lower incidence/higher age onset of AD? 2) What fraction of AD patients were taking vasodilators before their AD was diagnosed? For example, Losartan is a widely prescribed angiotensin II blocker, with around 50 million prescriptions per year. It should be possible to sample this pool to determine the incidence of AD among this population.

    Competing Interests: None declared.
  • Potential role of Nox1 for endothelin-dependent capillary vasoconstriction in Alzheimer's disease and dementia
    • Matthias Barton, University of Zurich, Switzerland and Andreas Grüntzig Foundation, Switzerland
    • Other Contributors:
      • Matthias R. Meyer, University of Zurich, Switzerland, and Triemli City Hospital, Zurich, Switzerland
      • Eric R. Prossnitz, Department of Internal Medicine and University of New Mexico Comprehensive Cancer Center, U.S.A.

    With interest we read the report by Nortley et al. identifying amyloid β1-42 (Aβ)-induced vasoconstriction of brain capillaries as a novel pathomechanism underlying Alzheimer's disease (AD) (1). The authors also report that pericyte constriction of human brain capillaries increases with Aβ load, and that NADPH oxidase (Nox) inhibitor GKT137831 or endothelin ETA receptor antagonist BQ-123 reversed Aβ-induced vasoconstriction. This study links chronic hypoperfusion due to vasoconstriction with loss of functional brain tissue in AD, a mechanism likely also contributing to hypertensive or atherosclerotic forms of dementia (2). The authors' conclusions are based on indirect evidence obtained with inhibitory substances. Nox4 is expressed in multiple cell types (3), including endothelial cells that the authors also studied. Endothelial Nox4 activates eNOS to produce NO (3) and generates both, O2- and H2O2, a vasodilator with pressure-lowering effects (4). Under healthy conditions Nox4 is the predominant isoform in human pericytes, whereas cellular stress also induces other Nox isoforms (5). Nox1, formerly "Mox1" (mitogenic oxidase) (6), expressed in both, pericytes (7) and their functional homologue, vascular smooth muscle cells (6, 8), propagates vasoconstriction, inflammation, and fibrosis (8, 9). While the authors refer to GKT137831 as a "Nox4 inhibitor", it blocks both, Nox1 and Nox4 (10). Because Nox1 was concomitantly blocked and neither Nox1 n...

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    Competing Interests: The authors are inventors on patents or patent applications related to targeting GPER.
  • RE: SOD1 and SOD-mimetics as Alzheimer's Treatments

    This paper has immediate and direct application to the prevention and treatment of Alzheimers, a disease with a dismal prognosis. First, the vasodilating drugs sildenafil and tadalfil are currently being repurposed for Alzheimers, as well as for vascular dementia. E.g., the PASTIS trial. Similarly, as "Orgotein", SOD1 had regulatory approval in some countries for the treatment of, e.g., Peyronies, interstitial cystitis, and as a radioprotectant While SOD1 must be given by injection, small-molecule neuroprotectant SOD-mimetics such as Tempol are orally effective and similarly non-toxic . Raising levels of the naturally-occurring antioxidant uric acid (e.g., by inosine supplementation) may also be useful in treating Alzheimers

    Competing Interests: Current have or in the past have had patents covering nitroxide spin traps (e.g., Tempol) and spin labels (e.g., PBN).

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