{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T13:49:32Z","timestamp":1792072172974,"version":"4.4.0"},"reference-count":97,"publisher":"Rockefeller University Press","issue":"6","license":[{"start":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"NIH National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG066645"],"award-info":[{"award-number":["R01AG066645"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["DP2NS121347"],"award-info":[{"award-number":["DP2NS121347"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["5F31NS139505"],"award-info":[{"award-number":["5F31NS139505"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS138179"],"award-info":[{"award-number":["R01NS138179"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R21NS142439"],"award-info":[{"award-number":["R21NS142439"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014989","name":"Chan Zuckerberg Initiative","doi-asserted-by":"publisher","award":["CP2-1-0000000385"],"award-info":[{"award-number":["CP2-1-0000000385"]}],"id":[{"id":"10.13039\/100014989","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["830093"],"award-info":[{"award-number":["830093"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"name":"D.C. Women's Board","award":["https:\/\/doi.org\/10.58275\/AHA.26CDA1592450.pc.gr.243187"],"award-info":[{"award-number":["https:\/\/doi.org\/10.58275\/AHA.26CDA1592450.pc.gr.243187"]}]},{"name":"D.C. Women's Board","award":["26CDA1592450"],"award-info":[{"award-number":["26CDA1592450"]}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,11,2]]},"abstract":"<jats:p>In Alzheimer\u2019s disease (AD), vascular dysfunction and impaired control of brain blood flow can disrupt cellular bioenergetics decades before cognitive decline. Identifying the earliest vascular changes is therefore critical for developing therapies that intervene before the cascading events leading to neuronal decline. Brain energy supply is dynamically controlled by the cerebral vasculature, where capillary thin-strand pericytes are emerging as key players. We recently identified a central role for ATP-sensitive potassium (K+, KATP) channels in enabling thin-strand pericytes to sense local neuronal activity and generate hyperpolarizing signals that are transmitted via capillary endothelial cells to upstream arterioles, eliciting increases in blood flow. Importantly, thin-strand pericyte KATP channels are the centerpiece of an electro-metabolic \u201cenergy switch\u201d mechanism that couples decreases in local glucose to hyperemia, providing a failsafe to ensure continual energy substrate supply to support neuronal function. Disruption of this mechanism could therefore precipitate an imbalance between demand and supply, creating an energy gap for neurons that leads to deleterious consequences. We demonstrate that capillary control of blood flow is disrupted in the early stages of disease progression in mice expressing familial AD mutations (5xFAD). Transgenic 5xFAD mice exhibit early disruption of capillary signaling, beginning with dysfunctional endothelial inward rectifier K+ (Kir)2.1 channels at 2\u20134 mo, disabling transmission of KATP-mediated signals to upstream blood flow control machinery, followed by direct impairment of pericyte KATP channel function by 6\u20138 mo. Together, these deficits cause early and sustained failure of electrical signaling from deep capillary pericytes to upstream arterioles and arteriole\u2013capillary transition (ACT) zone vessels, limiting KATP-dependent energy-switch-mediated blood flow control. Our findings define a temporal and mechanistic framework linking familial AD mutations to early capillary signaling dysfunction and highlight preservation of capillary blood flow control as a potential therapeutic target to protect against downstream effects of amyloid \u03b2 accumulation.<\/jats:p>","DOI":"10.1085\/jgp.202614014","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T06:20:35Z","timestamp":1789712435000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Early disruptions in brain capillary blood flow control in a mouse model of Alzheimer\u2019s disease"],"prefix":"10.1085","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1734-4443","authenticated-orcid":true,"given":"Ashwini","family":"Hariharan","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04rq5mt64","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Maryland School of Medicine 1 Department of Pharmacology & Physiology, , Baltimore, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2640-7728","authenticated-orcid":true,"given":"Abigail","family":"Vigderman","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04rq5mt64","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Maryland School of Medicine 1 Department of Pharmacology & Physiology, , Baltimore, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8828-5957","authenticated-orcid":true,"given":"Dominic P.","family":"Isaacs","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04rq5mt64","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Maryland School of Medicine 1 Department of Pharmacology & Physiology, , Baltimore, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5133-7832","authenticated-orcid":true,"given":"Nick","family":"Weir","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04rq5mt64","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Maryland School of Medicine 1 Department of Pharmacology & Physiology, , Baltimore, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6046-9914","authenticated-orcid":true,"given":"Gyubyung","family":"Park","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04rq5mt64","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Maryland School of Medicine 1 Department of Pharmacology & Physiology, , Baltimore, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5991-6127","authenticated-orcid":true,"given":"Serena","family":"Edwards","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04rq5mt64","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Maryland School of Medicine 1 Department of Pharmacology & Physiology, , Baltimore, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7950-7677","authenticated-orcid":true,"given":"Thomas A.","family":"Longden","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04rq5mt64","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Maryland School of Medicine 1 Department of Pharmacology & Physiology, , Baltimore, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,10,15]]},"reference":[{"key":"2026101509241798900_bib1","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1002\/iub.246","article-title":"Molecular biology of K(ATP) channels and implications for health and disease","volume":"61","author":"Akrouh","year":"2009","journal-title":"IUBMB Life"},{"key":"2026101509241798900_bib2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202504175","article-title":"Aberrant mitochondrial metabolism in Alzheimer\u2019s disease links energy stress with ferroptosis","volume":"12","author":"Alves","year":"2025","journal-title":"Adv. Sci."},{"key":"2026101509241798900_bib3","doi-asserted-by":"publisher","first-page":"609","DOI":"10.3233\/JAD-181238","article-title":"The time course of recognition memory impairment and glial pathology in the hAPP-J20 mouse model of Alzheimer\u2019s disease","volume":"68","author":"Ameen-Ali","year":"2019","journal-title":"J. Alzheimers Dis."},{"key":"2026101509241798900_bib4","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1097\/00004647-200110000-00001","article-title":"An energy budget for signaling in the grey matter of the brain","volume":"21","author":"Attwell","year":"2001","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"2026101509241798900_bib5","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1038\/85525","article-title":"Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy","volume":"7","author":"Bacskai","year":"2001","journal-title":"Nat. Med."},{"key":"2026101509241798900_bib6","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.3390\/life13041053","article-title":"Brain region-specific differences in amyloid-\u03b2 plaque composition in 5XFAD mice","volume":"13","author":"Bader","year":"2023","journal-title":"Life (Basel)"},{"key":"2026101509241798900_bib7","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1038\/s41591-020-0781-z","article-title":"A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer\u2019s disease","volume":"26","author":"Barth\u00e9lemy","year":"2020","journal-title":"Nat. Med."},{"key":"2026101509241798900_bib8","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12873","article-title":"Temporal and regional progression of Alzheimer\u2019s disease-like pathology in 3xTg-AD mice","volume":"18","author":"Belfiore","year":"2019","journal-title":"Aging Cell"},{"key":"2026101509241798900_bib9","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1038\/nn.2100","article-title":"Oligomeric amyloid-beta peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism","volume":"11","author":"Berman","year":"2008","journal-title":"Nat. Neurosci."},{"key":"2026101509241798900_bib10","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.celrep.2017.12.016","article-title":"Dynamic remodeling of pericytes in vivo maintains capillary coverage in the adult mouse brain","volume":"22","author":"Berthiaume","year":"2018","journal-title":"Cell Rep."},{"key":"2026101509241798900_bib11","doi-asserted-by":"publisher","first-page":"100431","DOI":"10.1016\/j.crmeth.2023.100431","article-title":"A robust and efficient microvascular isolation method for multimodal characterization of the mouse brain vasculature","volume":"3","author":"Bj\u00f8rnholm","year":"2023","journal-title":"Cell Rep. Methods"},{"key":"2026101509241798900_bib12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2321021121","article-title":"Capillary regression leads to sustained local hypoperfusion by inducing constriction of upstream transitional vessels","volume":"121","author":"Bonney","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026101509241798900_bib13","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1177\/0271678X251313906","article-title":"Control of neurovascular coupling by ATP-sensitive potassium channels","volume":"45","author":"Bowen","year":"2025","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"2026101509241798900_bib14","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1097\/NEN.0b013e318232a379","article-title":"Stages of the pathologic process in Alzheimer disease: Age categories from 1 to 100 years","volume":"70","author":"Braak","year":"2011","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"2026101509241798900_bib15","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.jalz.2007.10.015","article-title":"Elevated microsomal prostaglandin-E synthase-1 in Alzheimer\u2019s disease","volume":"4","author":"Chaudhry","year":"2008","journal-title":"Alzheimers Dement."},{"key":"2026101509241798900_bib16","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1023\/a:1007509608440","article-title":"Interaction of amyloid beta-protein with anionic phospholipids: Possible involvement of Lys28 and C-terminus aliphatic amino acids","volume":"25","author":"Chauhan","year":"2000","journal-title":"Neurochem. Res."},{"key":"2026101509241798900_bib17","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1038\/s41398-022-02132-4","article-title":"Early impairment of cortical circuit plasticity and connectivity in the 5XFAD Alzheimer\u2019s disease mouse model","volume":"12","author":"Chen","year":"2022","journal-title":"Transl. Psychiatry"},{"key":"2026101509241798900_bib18","doi-asserted-by":"crossref","DOI":"10.4199\/C00005ED1V01Y200912ISP002","volume-title":"The Cerebral Circulation","author":"Cipolla","year":"2009"},{"key":"2026101509241798900_bib19","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1038\/s41593-018-0329-4","article-title":"Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer\u2019s disease mouse models","volume":"22","author":"Cruz Hern\u00e1ndez","year":"2019","journal-title":"Nat. Neurosci."},{"key":"2026101509241798900_bib20","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2025998118","article-title":"PIP2 corrects cerebral blood flow deficits in small vessel disease by rescuing capillary Kir2.1 activity","volume":"118","author":"Dabertrand","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026101509241798900_bib21","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1212\/WNL.0b013e318227b227","article-title":"Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline","volume":"77","author":"Debette","year":"2011","journal-title":"Neurology"},{"key":"2026101509241798900_bib22","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1152\/physrev.00062.2017","article-title":"Brain glucose metabolism: Integration of energetics with function","volume":"99","author":"Dienel","year":"2019","journal-title":"Physiol. Rev."},{"key":"2026101509241798900_bib23","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1016\/j.tins.2022.08.004","article-title":"Neurovascular coupling: Motive unknown","volume":"45","author":"Drew","year":"2022","journal-title":"Trends Neurosci."},{"key":"2026101509241798900_bib24","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1111\/gbb.12133","article-title":"Abnormal vibrissa-related behavior and loss of barrel field inhibitory neurons in 5xFAD transgenics","volume":"13","author":"Flanigan","year":"2014","journal-title":"Genes Brain Behav."},{"key":"2026101509241798900_bib25","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/s41597-021-01054-y","article-title":"Systematic phenotyping and characterization of the 5xFAD mouse model of Alzheimer\u2019s disease","volume":"8","author":"Forner","year":"2021","journal-title":"Sci. Data"},{"key":"2026101509241798900_bib26","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1038\/s42003-019-0599-8","article-title":"3D mapping reveals network-specific amyloid progression and subcortical susceptibility in mice","volume":"2","author":"Gail Canter","year":"2019","journal-title":"Commun. Biol."},{"key":"2026101509241798900_bib27","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.nbd.2016.01.001","article-title":"Cerebrovascular pathology during the progression of experimental Alzheimer\u2019s disease","volume":"88","author":"Giannoni","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"2026101509241798900_bib28","doi-asserted-by":"publisher","first-page":"104570","DOI":"10.1016\/j.nbd.2019.104570","article-title":"Synaptic and memory dysfunction in a \u03b2-amyloid model of early Alzheimer\u2019s disease depends on increased formation of ATP-derived extracellular adenosine","volume":"132","author":"Gon\u00e7alves","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"2026101509241798900_bib29","doi-asserted-by":"publisher","first-page":"1443","DOI":"10.1001\/jama.2017.3090","article-title":"Association between midlife vascular risk factors and estimated brain amyloid deposition","volume":"317","author":"Gottesman","year":"2017","journal-title":"JAMA"},{"key":"2026101509241798900_bib30","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1177\/0271678X17732229","article-title":"Organizational hierarchy and structural diversity of microvascular pericytes in adult mouse cortex","volume":"39","author":"Grant","year":"2019","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"2026101509241798900_bib31","doi-asserted-by":"publisher","DOI":"10.1111\/gbb.12532","article-title":"Whisker exploration behaviours in the 5xFAD mouse are affected by sex and retinal degeneration","volume":"19","author":"Grant","year":"2020","journal-title":"Genes Brain Behav."},{"key":"2026101509241798900_bib32","doi-asserted-by":"publisher","first-page":"fcaf163","DOI":"10.1093\/braincomms\/fcaf163","article-title":"Vascular risk factor associations with subjective cognitive decline and mild behavioural impairment","volume":"7","author":"Guan","year":"2025","journal-title":"Brain Commun."},{"key":"2026101509241798900_bib33","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/nature13165","article-title":"Capillary pericytes regulate cerebral blood flow in health and disease","volume":"508","author":"Hall","year":"2014","journal-title":"Nature"},{"key":"2026101509241798900_bib34","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/nature10370","article-title":"Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2","volume":"477","author":"Hansen","year":"2011","journal-title":"Nature"},{"key":"2026101509241798900_bib35","doi-asserted-by":"publisher","first-page":"601324","DOI":"10.3389\/fncel.2020.601324","article-title":"The ion channel and GPCR toolkit of brain capillary pericytes","volume":"14","author":"Hariharan","year":"2020","journal-title":"Front. Cell. Neurosci."},{"key":"2026101509241798900_bib36","doi-asserted-by":"publisher","first-page":"111872","DOI":"10.1016\/j.celrep.2022.111872","article-title":"Brain capillary pericytes are metabolic sentinels that control blood flow through a KATP channel-dependent energy switch","volume":"41","author":"Hariharan","year":"2022","journal-title":"Cell Rep"},{"key":"2026101509241798900_bib38","doi-asserted-by":"publisher","first-page":"E3569","DOI":"10.1073\/pnas.1800201115","article-title":"Endothelial GqPCR activity controls capillary electrical signaling and brain blood flow through PIP2 depletion","volume":"115","author":"Harraz","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026101509241798900_bib39","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.38689","article-title":"PIP2 depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cells","volume":"7","author":"Harraz","year":"2018","journal-title":"Elife"},{"key":"2026101509241798900_bib40","doi-asserted-by":"publisher","first-page":"20378","DOI":"10.1073\/pnas.2006737117","article-title":"PIP2: A critical regulator of vascular ion channels hiding in plain sight","volume":"117","author":"Harraz","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026101509241798900_bib41","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1038\/s41593-020-00793-2","article-title":"Brain capillary pericytes exert a substantial but slow influence on blood flow","volume":"24","author":"Hartmann","year":"2021","journal-title":"Nat. Neurosci."},{"key":"2026101509241798900_bib42","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1146\/annurev-physiol-061121-040127","article-title":"Pericyte control of blood flow across microvascular zones in the central nervous system","volume":"84","author":"Hartmann","year":"2022","journal-title":"Annu. Rev. Physiol."},{"key":"2026101509241798900_bib43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2522750122","article-title":"PIP2 corrects an endothelial Piezo1 channelopathy","volume":"122","author":"Hashad","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026101509241798900_bib44","doi-asserted-by":"publisher","first-page":"180160","DOI":"10.1038\/sdata.2018.160","article-title":"Single-cell RNA sequencing of mouse brain and lung vascular and vessel-associated cell types","volume":"5","author":"He","year":"2018","journal-title":"Sci. Data"},{"key":"2026101509241798900_bib45","doi-asserted-by":"publisher","first-page":"re19","DOI":"10.1126\/stke.2001.111.re19","article-title":"The complex and intriguing lives of PIP2 with ion channels and transporters","volume":"2001","author":"Hilgemann","year":"2001","journal-title":"Sci. STKE"},{"key":"2026101509241798900_bib46","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1111\/jnc.14725","article-title":"The role of pericytes in brain disorders: From the periphery to the brain","volume":"150","author":"Hirunpattarasilp","year":"2019","journal-title":"J. Neurochem."},{"key":"2026101509241798900_bib47","doi-asserted-by":"publisher","first-page":"2089","DOI":"10.1177\/0271678X18780602","article-title":"A critical role for the ATP-sensitive potassium channel subunit KIR6.1 in the control of cerebral blood flow","volume":"39","author":"Hosford","year":"2019","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"2026101509241798900_bib48","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1038\/35882","article-title":"Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gbetagamma","volume":"391","author":"Huang","year":"1998","journal-title":"Nature"},{"key":"2026101509241798900_bib49","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2405965121","article-title":"KATP channel-dependent electrical signaling links capillary pericytes to arterioles during neurovascular coupling","volume":"121","author":"Isaacs","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026101509241798900_bib50","doi-asserted-by":"publisher","first-page":"11934","DOI":"10.1038\/ncomms11934","article-title":"Early role of vascular dysregulation on late-onset Alzheimer\u2019s disease based on multifactorial data-driven analysis","volume":"7","author":"Iturria-Medina","year":"2016","journal-title":"Nat. Commun."},{"key":"2026101509241798900_bib51","doi-asserted-by":"publisher","first-page":"1355","DOI":"10.1093\/brain\/awp062","article-title":"Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer\u2019s disease: Implications for sequence of pathological events in Alzheimer\u2019s disease","volume":"132","author":"Jack","year":"2009","journal-title":"Brain"},{"key":"2026101509241798900_bib52","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1038\/s41591-020-0815-6","article-title":"Large-scale proteomic analysis of Alzheimer\u2019s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation","volume":"26","author":"Johnson","year":"2020","journal-title":"Nat. Med."},{"key":"2026101509241798900_bib53","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1038\/emm.2007.89","article-title":"ATP released from beta-amyloid-stimulated microglia induces reactive oxygen species production in an autocrine fashion","volume":"39","author":"Kim","year":"2007","journal-title":"Exp. Mol. Med."},{"key":"2026101509241798900_bib54","doi-asserted-by":"publisher","first-page":"1406","DOI":"10.1016\/j.jalz.2018.03.011","article-title":"Midlife vascular risk factors and midlife cognitive status in relation to prevalence of mild cognitive impairment and dementia in later life: The Atherosclerosis Risk in Communities Study","volume":"14","author":"Knopman","year":"2018","journal-title":"Alzheimers Dement."},{"key":"2026101509241798900_bib55","doi-asserted-by":"publisher","first-page":"2086","DOI":"10.1038\/s41593-024-01753-w","article-title":"Inhibiting Ca2+ channels in Alzheimer\u2019s disease model mice relaxes pericytes, improves cerebral blood flow and reduces immune cell stalling and hypoxia","volume":"27","author":"Korte","year":"2024","journal-title":"Nat. Neurosci."},{"key":"2026101509241798900_bib56","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1038\/s41421-020-0180-0","article-title":"The pericyte connectome: Spatial precision of neurovascular coupling is driven by selective connectivity maps of pericytes and endothelial cells and is disrupted in diabetes","volume":"6","author":"Kovacs-Oller","year":"2020","journal-title":"Cell Discov."},{"key":"2026101509241798900_bib57","doi-asserted-by":"publisher","first-page":"5003","DOI":"10.1016\/j.cell.2025.06.030","article-title":"Brain endothelial gap junction coupling enables rapid vasodilation propagation during neurovascular coupling","volume":"188","author":"Krolak","year":"2025","journal-title":"Cell"},{"key":"2026101509241798900_bib58","doi-asserted-by":"publisher","first-page":"626636","DOI":"10.3389\/fnins.2021.626636","article-title":"A systematic review of glucose transport alterations in Alzheimer\u2019s disease","volume":"15","author":"Kyrtata","year":"2021","journal-title":"Front. Neurosci."},{"key":"2026101509241798900_bib59","doi-asserted-by":"publisher","first-page":"19524","DOI":"10.1073\/pnas.0604954103","article-title":"Presenilin mutations linked to familial Alzheimer\u2019s disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism","volume":"103","author":"Landman","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026101509241798900_bib60","doi-asserted-by":"publisher","first-page":"4432","DOI":"10.1016\/j.bpj.2024.12.025","article-title":"Amyloid beta A\u03b21-40 activates Piezo1 channels in brain capillary endothelial cells","volume":"124","author":"Lim","year":"2025","journal-title":"Biophys. J."},{"key":"2026101509241798900_bib61","doi-asserted-by":"publisher","first-page":"1579","DOI":"10.1177\/0271678X20964233","article-title":"Age-related impairment of cerebral blood flow response to KATP channel opener in Alzheimer\u2019s disease mice with presenilin-1 mutation","volume":"41","author":"Liu","year":"2021","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"2026101509241798900_bib62","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1038\/nn.4533","article-title":"Capillary K+-sensing initiates retrograde hyperpolarization to increase local cerebral blood flow","volume":"20","author":"Longden","year":"2017","journal-title":"Nat. Neurosci."},{"key":"2026101509241798900_bib63","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1146\/annurev-physiol-031522-034807","article-title":"Pericytes and the control of blood flow in brain and heart","volume":"85","author":"Longden","year":"2023","journal-title":"Annu. Rev. Physiol."},{"key":"2026101509241798900_bib64","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.202313451","article-title":"Electro-metabolic signaling","volume":"156","author":"Longden","year":"2024","journal-title":"J. Gen. Physiol."},{"key":"2026101509241798900_bib65","doi-asserted-by":"publisher","first-page":"C1220","DOI":"10.1152\/ajpcell.00065.2026","article-title":"Cerebral capillary computation","volume":"330","author":"Longden","year":"2026","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"2026101509241798900_bib66","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1251-23.2024","article-title":"Super-resolution ultrasound reveals cerebrovascular impairment in a mouse model of Alzheimer\u2019s disease","volume":"44","author":"Lowerison","year":"2024","journal-title":"J. Neurosci."},{"key":"2026101509241798900_bib67","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4137\/BCI.S13025","article-title":"Molecular differences and similarities between Alzheimer\u2019s disease and the 5XFAD transgenic mouse model of amyloidosis","volume":"6","author":"Maarouf","year":"2013","journal-title":"Biochem. Insights."},{"key":"2026101509241798900_bib68","doi-asserted-by":"publisher","first-page":"24560","DOI":"10.1038\/srep24560","article-title":"Abnormal population responses in the somatosensory cortex of Alzheimer\u2019s disease model mice","volume":"6","author":"Maatuf","year":"2016","journal-title":"Sci. Rep."},{"key":"2026101509241798900_bib69","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1007\/s00259-005-1762-7","article-title":"Brain glucose metabolism in the early and specific diagnosis of Alzheimer's disease. FDG-PET studies in MCI and AD","volume":"32","author":"Mosconi","year":"2005","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"2026101509241798900_bib70","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1007\/s40336-013-0026-y","article-title":"Glucose metabolism in normal aging and Alzheimer\u2019s disease: Methodological and physiological considerations for PET studies","volume":"1","author":"Mosconi","year":"2013","journal-title":"Clin. Transl. Imaging"},{"key":"2026101509241798900_bib71","doi-asserted-by":"publisher","first-page":"zqab010","DOI":"10.1093\/function\/zqab010","article-title":"PIP2 improves cerebral blood flow in a mouse model of Alzheimer\u2019s disease","volume":"2","author":"Mughal","year":"2021","journal-title":"Function (Oxf)"},{"key":"2026101509241798900_bib72","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav9518","article-title":"Amyloid \u03b2 oligomers constrict human capillaries in Alzheimer\u2019s disease via signaling to pericytes","volume":"365","author":"Nortley","year":"2019","journal-title":"Science"},{"key":"2026101509241798900_bib73","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2615120123","article-title":"Endothelial Arf6 sustains electrical signaling and cerebral blood flow in mice through PIP2-dependent activation of Kir2.1 channels","volume":"123","author":"Noterman-Soulinthavong","year":"2026","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026101509241798900_bib74","doi-asserted-by":"publisher","first-page":"10129","DOI":"10.1523\/JNEUROSCI.1202-06.2006","article-title":"Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer\u2019s disease mutations: Potential factors in amyloid plaque formation","volume":"26","author":"Oakley","year":"2006","journal-title":"J. Neurosci."},{"key":"2026101509241798900_bib75","doi-asserted-by":"publisher","first-page":"713726","DOI":"10.3389\/fnagi.2021.713726","article-title":"Comprehensive evaluation of the 5XFAD mouse model for preclinical testing applications: A MODEL-AD study","volume":"13","author":"Oblak","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"2026101509241798900_bib76","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s42003-023-04858-3","article-title":"Orai, RyR, and IP3R channels cooperatively regulate calcium signaling in brain mid-capillary pericytes","volume":"6","author":"Phillips","year":"2023","journal-title":"Commun. Biol."},{"key":"2026101509241798900_bib77","doi-asserted-by":"publisher","first-page":"780","DOI":"10.3390\/cells12050780","article-title":"Sex differences between neuronal loss and the early onset of amyloid deposits and behavioral consequences in 5xFAD transgenic mouse as a model for Alzheimer\u2019s disease","volume":"12","author":"Poon","year":"2023","journal-title":"Cells"},{"key":"2026101509241798900_bib78","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.3233\/JAD-143120","article-title":"Gene dosage dependent aggravation of the neurological phenotype in the 5XFAD mouse model of Alzheimer\u2019s disease","volume":"45","author":"Richard","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"2026101509241798900_bib79","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1016\/j.neuron.2018.06.012","article-title":"Vascular compartmentalization of functional hyperemia from the synapse to the pia","volume":"99","author":"Rungta","year":"2018","journal-title":"Neuron"},{"key":"2026101509241798900_bib80","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.abl5405","article-title":"Adenosine signaling activates ATP-sensitive K+ channels in endothelial cells and pericytes in CNS capillaries","volume":"15","author":"Sancho","year":"2022","journal-title":"Sci. Signal."},{"key":"2026101509241798900_bib81","doi-asserted-by":"publisher","first-page":"4378","DOI":"10.4049\/jimmunol.0803612","article-title":"Activation of microglia by amyloid {beta} requires P2X7 receptor expression","volume":"182","author":"Sanz","year":"2009","journal-title":"J. Immunol."},{"key":"2026101509241798900_bib82","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.80442","article-title":"Navigating the future of elderly healthcare: A comprehensive analysis of aging populations and mortality trends using National Inpatient sample (NIS) data (2010-2024)","volume":"17","author":"Shreya","year":"2025","journal-title":"Cureus"},{"key":"2026101509241798900_bib83","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1093\/brain\/awad401","article-title":"Continued dysfunction of capillary pericytes promotes no-reflow after experimental stroke in vivo","volume":"147","author":"Shrouder","year":"2024","journal-title":"Brain"},{"key":"2026101509241798900_bib84","doi-asserted-by":"publisher","first-page":"755","DOI":"10.3233\/JAD-210523","article-title":"Sex differences in behavior and molecular pathology in the 5XFAD model","volume":"85","author":"Sil","year":"2022","journal-title":"J. Alzheimers Dis."},{"key":"2026101509241798900_bib85","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1002\/ana.410350507","article-title":"Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer\u2019s disease","volume":"35","author":"Simpson","year":"1994","journal-title":"Ann. Neurol."},{"key":"2026101509241798900_bib86","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1111\/j.1471-4159.1987.tb05619.x","article-title":"Reduced phosphoinositide concentrations in anterior temporal cortex of Alzheimer-diseased brains","volume":"48","author":"Stokes","year":"1987","journal-title":"J. Neurochem."},{"key":"2026101509241798900_bib87","doi-asserted-by":"publisher","first-page":"57556","DOI":"10.18632\/oncotarget.11353","article-title":"Spatial learning and memory impairments are associated with increased neuronal activity in 5XFAD mouse as measured by manganese-enhanced magnetic resonance imaging","volume":"7","author":"Tang","year":"2016","journal-title":"Oncotarget"},{"key":"2026101509241798900_bib88","doi-asserted-by":"publisher","DOI":"10.1113\/JP289276","article-title":"Amyloid \u03b2 alters vascular CaV1.2 channel spatiotemporal properties","author":"Taylor","year":"2026","journal-title":"J. Physiol."},{"key":"2026101509241798900_bib89","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2306479120","article-title":"PI3K block restores age-dependent neurovascular coupling defects associated with cerebral small vessel disease","volume":"120","author":"Thakore","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2026101509241798900_bib90","doi-asserted-by":"publisher","first-page":"4705","DOI":"10.1523\/JNEUROSCI.0169-12.2012","article-title":"Age-dependent rescue by simvastatin of Alzheimer\u2019s disease cerebrovascular and memory deficits","volume":"32","author":"Tong","year":"2012","journal-title":"J. Neurosci."},{"key":"2026101509241798900_bib91","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1038\/nature25739","article-title":"A molecular atlas of cell types and zonation in the brain vasculature","volume":"554","author":"Vanlandewijck","year":"2018","journal-title":"Nature"},{"key":"2026101509241798900_bib92","doi-asserted-by":"publisher","first-page":"2122","DOI":"10.1002\/cne.24555","article-title":"Whole brain imaging reveals distinct spatial patterns of amyloid beta deposition in three mouse models of Alzheimer\u2019s disease","volume":"527","author":"Whitesell","year":"2019","journal-title":"J. Comp. Neurol."},{"key":"2026101509241798900_bib93","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2523612123","article-title":"A pericyte chloride clamp mechanism governs capillary control of cerebral blood flow","volume":"123","author":"Xiang","year":"2026","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026101509241798900_bib94","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1186\/s13024-023-00634-3","article-title":"Axonal energy metabolism, and the effects in aging and neurodegenerative diseases","volume":"18","author":"Yang","year":"2023","journal-title":"Mol. Neurodegener."},{"key":"2026101509241798900_bib95","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1038\/nm.2022","article-title":"Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery","volume":"15","author":"Yemisci","year":"2009","journal-title":"Nat. Med."},{"key":"2026101509241798900_bib96","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2023749118","article-title":"Precapillary sphincters and pericytes at first-order capillaries as key regulators for brain capillary perfusion","volume":"118","author":"Zambach","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026101509241798900_bib97","doi-asserted-by":"publisher","first-page":"375","DOI":"10.3233\/JAD-141890","article-title":"Characterization of ATP alternations in an Alzheimer\u2019s disease transgenic mouse model","volume":"44","author":"Zhang","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"2026101509241798900_bib98","doi-asserted-by":"publisher","first-page":"11965","DOI":"10.1073\/pnas.1510011112","article-title":"Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer\u2019s disease pathogenesis","volume":"112","author":"Zhu","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Journal of General Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jgp\/article-pdf\/doi\/10.1085\/jgp.202614014\/2041865\/jgp_202614014.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jgp\/article-pdf\/doi\/10.1085\/jgp.202614014\/2041865\/jgp_202614014.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T13:24:34Z","timestamp":1792070674000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jgp\/article\/158\/6\/e202614014\/283067\/Early-disruptions-in-brain-capillary-blood-flow"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,15]]},"references-count":97,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,11,2]]}},"URL":"https:\/\/doi.org\/10.1085\/jgp.202614014","relation":{},"ISSN":["0022-1295","1540-7748"],"issn-type":[{"value":"0022-1295","type":"print"},{"value":"1540-7748","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,15]]},"article-number":"e202614014"}}