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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,6,28]]},"abstract":"<jats:p>\n                    The brain microcirculation is increasingly viewed as a potential target for disease-modifying drugs in the treatment of Alzheimer\u2019s disease patients, reflecting a growing appreciation of evidence that cerebral blood flow is compromised in such patients. However, the pathogenic mechanisms in brain resistance arteries underlying blood flow defects have not yet been elucidated. Here we probed the roles of principal vasodilatory pathways in cerebral arteries using the APP23 mouse model of Alzheimer\u2019s disease, in which amyloid precursor protein is increased approximately sevenfold, leading to neuritic plaques and cerebrovascular accumulation of amyloid-\u03b2 similar to those in patients with Alzheimer\u2019s disease. Pial arteries from APP23 mice (18 mo old) exhibited enhanced pressure-induced (myogenic) constriction because of a profound reduction in ryanodine receptor-mediated, local calcium-release events (\u201cCa\n                    <jats:sup>2+<\/jats:sup>\n                    sparks\u201d) in arterial smooth muscle cells and a consequent decrease in the activity of large-conductance Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -activated K\n                    <jats:sup>+<\/jats:sup>\n                    (BK) channels. The ability of the endothelial cell inward rectifier K\n                    <jats:sup>+<\/jats:sup>\n                    (Kir2.1) channel to cause dilation was also compromised. Acute application of amyloid-\u03b2 1-40 peptide to cerebral arteries from wild-type mice partially recapitulated the BK dysfunction seen in APP23 mice but had no effect on Kir2.1 function. If mirrored in human Alzheimer\u2019s disease, these tandem defects in K\n                    <jats:sup>+<\/jats:sup>\n                    channel-mediated vasodilation could account for the clinical cerebrovascular presentation seen in patients: reduced blood flow and crippled functional hyperemia. These data direct future research toward approaches that reverse this dual vascular channel dysfunction, with the ultimate aim of restoring healthy cerebral blood flow and improving clinical outcomes.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2204581119","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T15:03:30Z","timestamp":1655823810000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":46,"title":["Functionally linked potassium channel activity in cerebral endothelial and smooth muscle cells is compromised in Alzheimer\u2019s disease"],"prefix":"10.1073","volume":"119","author":[{"given":"Jade L.","family":"Taylor","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Sciences, Faculty of Biology, Medicine, and Health, University of Manchester &amp; Manchester University Teaching Hospitals NHS Foundation Trust, Manchester M13 9PL, United Kingdom"},{"name":"Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance NHS Group, University of Manchester, Manchester M13 9PL, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2408-0909","authenticated-orcid":false,"given":"Harry A. T.","family":"Pritchard","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Sciences, Faculty of Biology, Medicine, and Health, University of Manchester &amp; Manchester University Teaching Hospitals NHS Foundation Trust, Manchester M13 9PL, United Kingdom"},{"name":"Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance NHS Group, University of Manchester, Manchester M13 9PL, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katy R.","family":"Walsh","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Sciences, Faculty of Biology, Medicine, and Health, University of Manchester &amp; Manchester University Teaching Hospitals NHS Foundation Trust, Manchester M13 9PL, United Kingdom"},{"name":"Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance NHS Group, University of Manchester, Manchester M13 9PL, United Kingdom"},{"name":"Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine, and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PL, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Strangward","sequence":"additional","affiliation":[{"name":"Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance NHS Group, University of Manchester, Manchester M13 9PL, United Kingdom"},{"name":"Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine, and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PL, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"White","sequence":"additional","affiliation":[{"name":"Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance NHS Group, University of Manchester, Manchester M13 9PL, United Kingdom"},{"name":"Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine, and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PL, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hill-Eubanks","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, VT 05405"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariam","family":"Alakrawi","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Sciences, Faculty of Biology, Medicine, and Health, University of Manchester &amp; Manchester University Teaching Hospitals NHS Foundation Trust, Manchester M13 9PL, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant W.","family":"Hennig","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, VT 05405"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9646-4456","authenticated-orcid":false,"given":"Stuart M.","family":"Allan","sequence":"additional","affiliation":[{"name":"Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance NHS Group, University of Manchester, Manchester M13 9PL, United Kingdom"},{"name":"Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine, and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PL, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark 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A.","year":"2022","unstructured":"A. A. LaPlume, L. McKetton, N. D. Anderson, A. K. Troyer, Sex differences and modifiable dementia risk factors synergistically influence memory over the adult lifespan. Alzheimers Dement. (Amst.) 14, e12301 (2022).","journal-title":"Alzheimers Dement. 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