{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T17:47:20Z","timestamp":1783100840268,"version":"3.54.6"},"reference-count":86,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T00:00:00Z","timestamp":1737504000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T00:00:00Z","timestamp":1737504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"funder":[{"name":"NIH","award":["1R01AG081258-01A1"],"award-info":[{"award-number":["1R01AG081258-01A1"]}]},{"name":"NIH","award":["1RF1NS132291-01"],"award-info":[{"award-number":["1RF1NS132291-01"]}]},{"name":"NIH","award":["1R01AG081874-01"],"award-info":[{"award-number":["1R01AG081874-01"]}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["22TPA970253"],"award-info":[{"award-number":["22TPA970253"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["23POST1018945"],"award-info":[{"award-number":["23POST1018945"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["23CDA1051814"],"award-info":[{"award-number":["23CDA1051814"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["GeroScience"],"DOI":"10.1007\/s11357-025-01526-8","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T17:40:23Z","timestamp":1737567623000},"page":"4153-4167","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Blockade of A2AR improved brain perfusion and cognitive function in a mouse model of Alzheimer\u2019s disease"],"prefix":"10.1007","volume":"47","author":[{"given":"Mariana Sayuri Berto","family":"Udo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Zaccarelli-Magalh\u00e3es","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garrett Alan","family":"Clemons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiane Teresinha","family":"Citadin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Langman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Drew James","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luiz Henrique","family":"Matuguma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vesna","family":"Tesic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1010-5423","authenticated-orcid":false,"given":"Hung Wen","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,22]]},"reference":[{"key":"1526_CR1","doi-asserted-by":"crossref","unstructured":"2021 alzheimer's disease facts and figures. Alzheimers Dement. 2021;17:327-406","DOI":"10.1002\/alz.12328"},{"issue":"Suppl 2","key":"1526_CR2","doi-asserted-by":"publisher","first-page":"S527","DOI":"10.3233\/JAD-2010-100501","volume":"20","author":"J Vina","year":"2010","unstructured":"Vina J, Lloret A. Why women have more alzheimer\u2019s disease than men: Gender and mitochondrial toxicity of amyloid-beta peptide. J Alzheimers Dis. 2010;20(Suppl 2):S527-533.","journal-title":"J Alzheimers Dis"},{"key":"1526_CR3","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1161\/STROKEAHA.108.540781","volume":"40","author":"P Appelros","year":"2009","unstructured":"Appelros P, Stegmayr B, Terent A. Sex differences in stroke epidemiology: A systematic review. Stroke. 2009;40:1082\u201390.","journal-title":"Stroke"},{"issue":"Suppl 4","key":"1526_CR4","doi-asserted-by":"publisher","first-page":"S353","DOI":"10.3233\/JAD-141629","volume":"42","author":"C Dufouil","year":"2014","unstructured":"Dufouil C, Seshadri S, Chene G. Cardiovascular risk profile in women and dementia. J Alzheimers Dis. 2014;42(Suppl 4):S353-363.","journal-title":"J Alzheimers Dis"},{"key":"1526_CR5","doi-asserted-by":"publisher","first-page":"1970","DOI":"10.1161\/01.STR.0000083534.81284.C5","volume":"34","author":"EL Glader","year":"2003","unstructured":"Glader EL, Stegmayr B, Norrving B, Terent A, Hulter-Asberg K, Wester PO, et al. Sex differences in management and outcome after stroke: A swedish national perspective. Stroke. 2003;34:1970\u20135.","journal-title":"Stroke"},{"key":"1526_CR6","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.1016\/j.jalz.2018.04.008","volume":"14","author":"RA Nebel","year":"2018","unstructured":"Nebel RA, Aggarwal NT, Barnes LL, Gallagher A, Goldstein JM, Kantarci K, et al. Understanding the impact of sex and gender in alzheimer\u2019s disease: a call to action. Alzheimers Dement. 2018;14:1171\u201383.","journal-title":"Alzheimers Dement"},{"key":"1526_CR7","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s13195-016-0188-8","volume":"8","author":"M Prince","year":"2016","unstructured":"Prince M, Ali GC, Guerchet M, Prina AM, Albanese E, Wu YT. Recent global trends in the prevalence and incidence of dementia, and survival with dementia. Alzheimers Res Ther. 2016;8:23.","journal-title":"Alzheimers Res Ther"},{"key":"1526_CR8","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1007\/s00401-020-02215-w","volume":"140","author":"N Korte","year":"2020","unstructured":"Korte N, Nortley R, Attwell D. Cerebral blood flow decrease as an early pathological mechanism in alzheimer\u2019s disease. Acta Neuropathol. 2020;140:793\u2013810.","journal-title":"Acta Neuropathol"},{"key":"1526_CR9","doi-asserted-by":"publisher","first-page":"493","DOI":"10.2147\/CIA.S58879","volume":"9","author":"B Ding","year":"2014","unstructured":"Ding B, Ling HW, Zhang Y, Huang J, Zhang H, Wang T, et al. Pattern of cerebral hyperperfusion in alzheimer\u2019s disease and amnestic mild cognitive impairment using voxel-based analysis of 3d arterial spin-labeling imaging: Initial experience. Clin Interv Aging. 2014;9:493\u2013500.","journal-title":"Clin Interv Aging"},{"issue":"Suppl 3","key":"1526_CR10","doi-asserted-by":"publisher","first-page":"123","DOI":"10.3233\/JAD-2011-0010","volume":"26","author":"BP Austin","year":"2011","unstructured":"Austin BP, Nair VA, Meier TB, Xu G, Rowley HA, Carlsson CM, et al. Effects of hypoperfusion in alzheimer\u2019s disease. J Alzheimers Dis. 2011;26(Suppl 3):123\u201333.","journal-title":"J Alzheimers Dis"},{"key":"1526_CR11","doi-asserted-by":"publisher","first-page":"5789","DOI":"10.3390\/molecules25245789","volume":"25","author":"Z Breijyeh","year":"2020","unstructured":"Breijyeh Z, Karaman R. Comprehensive review on alzheimer\u2019s disease: Causes and treatment. Molecules. 2020;25:5789.","journal-title":"Molecules"},{"key":"1526_CR12","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1038\/jcbfm.2009.244","volume":"30","author":"Y Kusano","year":"2010","unstructured":"Kusano Y, Echeverry G, Miekisiak G, Kulik TB, Aronhime SN, Chen JF, et al. Role of adenosine a2 receptors in regulation of cerebral blood flow during induced hypotension. J Cereb Blood Flow Metab. 2010;30:808\u201315.","journal-title":"J Cereb Blood Flow Metab"},{"key":"1526_CR13","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.3233\/JAD-201437","volume":"80","author":"S Merighi","year":"2021","unstructured":"Merighi S, Battistello E, Casetta I, Gragnaniello D, Poloni TE, Medici V, et al. Upregulation of cortical a2a adenosine receptors is reflected in platelets of patients with alzheimer\u2019s disease. J Alzheimers Dis. 2021;80:1105\u201317.","journal-title":"J Alzheimers Dis"},{"key":"1526_CR14","doi-asserted-by":"publisher","first-page":"1720920","DOI":"10.1155\/2017\/1720920","volume":"2017","author":"MT Khayat","year":"2017","unstructured":"Khayat MT, Nayeem MA. The role of adenosine a(2a) receptor, cyp450s, and ppars in the regulation of vascular tone. Biomed Res Int. 2017;2017:1720920.","journal-title":"Biomed Res Int"},{"key":"1526_CR15","doi-asserted-by":"publisher","first-page":"14741","DOI":"10.1523\/JNEUROSCI.3728-09.2009","volume":"29","author":"PM Canas","year":"2009","unstructured":"Canas PM, Porciuncula LO, Cunha GM, Silva CG, Machado NJ, Oliveira JM, et al. Adenosine a2a receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p38 mitogen-activated protein kinase pathway. J Neurosci. 2009;29:14741\u201351.","journal-title":"J Neurosci"},{"key":"1526_CR16","first-page":"364364","volume":"11","author":"J Lee","year":"2022","unstructured":"Lee J, An S, Lee SJ, Kang JS. Protein arginine methyltransferases in neuromuscular function and diseases. Cells. 2022;11:364364.","journal-title":"Cells"},{"key":"1526_CR17","doi-asserted-by":"publisher","first-page":"e30858","DOI":"10.1002\/jcp.30858","volume":"239","author":"GA Clemons","year":"2024","unstructured":"Clemons GA, Silva ACE, Acosta CH, Udo MSB, Tesic V, Rodgers KM, et al. Protein arginine methyltransferase 4 modulates nitric oxide synthase uncoupling and cerebral blood flow in alzheimer\u2019s disease. J Cell Physiol. 2024;239:e30858.","journal-title":"J Cell Physiol"},{"key":"1526_CR18","doi-asserted-by":"publisher","first-page":"3000411","DOI":"10.1371\/journal.pbio.3000411","volume":"18","author":"N Percie du Sert","year":"2020","unstructured":"Percie du Sert N, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, et al. Reporting animal research: explanation and elaboration for the arrive guidelines 2.0. PLOS Biology. 2020;18:3000411.","journal-title":"PLOS Biology"},{"key":"1526_CR19","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1111\/jnc.15462","volume":"159","author":"ESA Couto","year":"2021","unstructured":"Couto ESA, Wu CY, Clemons GA, Acosta CH, Chen CT, Possoit HE, et al. Protein arginine methyltransferase 8 modulates mitochondrial bioenergetics and neuroinflammation after hypoxic stress. J Neurochem. 2021;159:742\u201361.","journal-title":"J Neurochem"},{"key":"1526_CR20","doi-asserted-by":"publisher","first-page":"1321","DOI":"10.1093\/cvr\/cvab155","volume":"118","author":"K O'Gallagher","year":"2022","unstructured":"O\u2019Gallagher K, Puledda F, O\u2019Daly O, Ryan M, Dancy L, Chowienczyk PJ, et al. Neuronal nitric oxide synthase regulates regional brain perfusion in healthy humans. Cardiovasc Res. 2022;118:1321\u20139.","journal-title":"Cardiovasc Res"},{"key":"1526_CR21","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1002\/alz.12406","volume":"18","author":"AC van Harten","year":"2022","unstructured":"van Harten AC, Wiste HJ, Weigand SD, Mielke MM, Kremers WK, Eichenlaub U, et al. Detection of alzheimer\u2019s disease amyloid beta 1\u201342, p-tau, and t-tau assays. Alzheimers Dement. 2022;18:635\u201344.","journal-title":"Alzheimers Dement"},{"key":"1526_CR22","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1007\/s10571-015-0261-z","volume":"36","author":"CC Hays","year":"2016","unstructured":"Hays CC, Zlatar ZZ, Wierenga CE. The utility of cerebral blood flow as a biomarker of preclinical alzheimer\u2019s disease. Cell Mol Neurobiol. 2016;36:167\u201379.","journal-title":"Cell Mol Neurobiol"},{"key":"1526_CR23","doi-asserted-by":"publisher","first-page":"e13061","DOI":"10.1111\/bpa.13061","volume":"32","author":"RA Fisher","year":"2022","unstructured":"Fisher RA, Miners JS, Love S. Pathological changes within the cerebral vasculature in alzheimer\u2019s disease: new perspectives. Brain pathology (Zurich, Switzerland). 2022;32:e13061.","journal-title":"Brain pathology (Zurich, Switzerland)"},{"key":"1526_CR24","doi-asserted-by":"publisher","first-page":"2697","DOI":"10.1093\/brain\/awt188","volume":"136","author":"JB Toledo","year":"2013","unstructured":"Toledo JB, Arnold SE, Raible K, Brettschneider J, Xie SX, Grossman M, et al. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the national alzheimer\u2019s coordinating centre. Brain. 2013;136:2697\u2013706.","journal-title":"Brain"},{"key":"1526_CR25","doi-asserted-by":"publisher","first-page":"fcaa114","DOI":"10.1093\/braincomms\/fcaa114","volume":"2","author":"GML Eglit","year":"2020","unstructured":"Eglit GML, Weigand AJ, Nation DA, Bondi MW, Bangen KJ. Hypertension and alzheimer\u2019s disease: Indirect effects through circle of willis atherosclerosis. Brain Commun. 2020;2:fcaa114.","journal-title":"Brain Commun"},{"key":"1526_CR26","doi-asserted-by":"publisher","first-page":"293","DOI":"10.3233\/JAD-210199","volume":"82","author":"W Duan","year":"2021","unstructured":"Duan W, Zhou GD, Balachandrasekaran A, Bhumkar AB, Boraste PB, Becker JT, et al. Cerebral blood flow predicts conversion of mild cognitive impairment into alzheimer\u2019s disease and cognitive decline: An arterial spin labeling follow-up study. J Alzheimers Dis. 2021;82:293\u2013305.","journal-title":"J Alzheimers Dis"},{"key":"1526_CR27","doi-asserted-by":"publisher","first-page":"1324522","DOI":"10.3389\/fgwh.2023.1324522","volume":"4","author":"MA O'Neal","year":"2023","unstructured":"O\u2019Neal MA. Women and the risk of alzheimer\u2019s disease. Front Glob Womens Health. 2023;4:1324522.","journal-title":"Front Glob Womens Health"},{"key":"1526_CR28","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1002\/alz.12694","volume":"19","author":"A Gustavsson","year":"2023","unstructured":"Gustavsson A, Norton N, Fast T, Frolich L, Georges J, Holzapfel D, et al. Global estimates on the number of persons across the alzheimer\u2019s disease continuum. Alzheimers Dement. 2023;19:658\u201370.","journal-title":"Alzheimers Dement"},{"key":"1526_CR29","first-page":"1199","volume":"25","author":"H Hanyu","year":"2004","unstructured":"Hanyu H, Shimizu S, Tanaka Y, Takasaki M, Koizumi K, Abe K. Differences in regional cerebral blood flow patterns in male versus female patients with alzheimer disease. AJNR Am J Neuroradiol. 2004;25:1199\u2013204.","journal-title":"AJNR Am J Neuroradiol"},{"key":"1526_CR30","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.2967\/jnumed.106.037218","volume":"48","author":"H Matsuda","year":"2007","unstructured":"Matsuda H. Role of neuroimaging in alzheimer\u2019s disease, with emphasis on brain perfusion spect. J Nucl Med. 2007;48:1289\u2013300.","journal-title":"J Nucl Med"},{"key":"1526_CR31","doi-asserted-by":"publisher","first-page":"143","DOI":"10.18632\/aging.203812","volume":"14","author":"YK Kang","year":"2022","unstructured":"Kang YK, Min B, Eom J, Park JS. Different phases of aging in mouse old skeletal muscle. Aging (Albany NY). 2022;14:143\u201360.","journal-title":"Aging (Albany NY)"},{"key":"1526_CR32","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.maturitas.2016.01.015","volume":"87","author":"SV Koebele","year":"2016","unstructured":"Koebele SV, Bimonte-Nelson HA. Modeling menopause: The utility of rodents in translational behavioral endocrinology research. Maturitas. 2016;87:5\u201317.","journal-title":"Maturitas"},{"key":"1526_CR33","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/S0896-6273(03)00434-3","volume":"39","author":"S Oddo","year":"2003","unstructured":"Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, et al. Triple-transgenic model of alzheimer\u2019s disease with plaques and tangles: Intracellular abeta and synaptic dysfunction. Neuron. 2003;39:409\u201321.","journal-title":"Neuron"},{"key":"1526_CR34","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/j.neuron.2005.01.040","volume":"45","author":"LM Billings","year":"2005","unstructured":"Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM. Intraneuronal abeta causes the onset of early alzheimer\u2019s disease-related cognitive deficits in transgenic mice. Neuron. 2005;45:675\u201388.","journal-title":"Neuron"},{"key":"1526_CR35","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.bbr.2015.04.012","volume":"289","author":"KR Stover","year":"2015","unstructured":"Stover KR, Campbell MA, Van Winssen CM, Brown RE. Early detection of cognitive deficits in the 3xtg-ad mouse model of alzheimer\u2019s disease. Behav Brain Res. 2015;289:29\u201338.","journal-title":"Behav Brain Res"},{"key":"1526_CR36","doi-asserted-by":"publisher","first-page":"785276","DOI":"10.3389\/fnins.2021.785276","volume":"15","author":"DI Javonillo","year":"2021","unstructured":"Javonillo DI, Tran KM, Phan J, Hingco E, Kram\u00e1r EA, da Cunha C, et al. Systematic phenotyping and characterization of the 3xtg-ad mouse model of alzheimer\u2019s disease. Front Neurosci. 2021;15:785276.","journal-title":"Front Neurosci"},{"key":"1526_CR37","doi-asserted-by":"publisher","first-page":"1343653","DOI":"10.3389\/fcell.2023.1343653","volume":"11","author":"E Shigetomi","year":"2023","unstructured":"Shigetomi E, Sakai K, Koizumi S. Extracellular atp\/adenosine dynamics in the brain and its role in health and disease. Front Cell Dev Biol. 2023;11:1343653.","journal-title":"Front Cell Dev Biol"},{"key":"1526_CR38","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1186\/s13195-023-01337-z","volume":"15","author":"Q Ji","year":"2023","unstructured":"Ji Q, Yang Y, Xiong Y, Zhang YJ, Jiang J, Zhou LP, et al. Blockade of adenosine a(2a) receptors reverses early spatial memory defects in the app\/ps1 mouse model of alzheimer\u2019s disease by promoting synaptic plasticity of adult-born granule cells. Alzheimers Res Ther. 2023;15:187.","journal-title":"Alzheimers Res Ther"},{"key":"1526_CR39","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1124\/pharmrev.121.000445","volume":"74","author":"AP Ij","year":"2022","unstructured":"Ij AP, Jacobson KA, Muller CE, Cronstein BN, Cunha RA. International union of basic and clinical pharmacology. Cxii: Adenosine receptors: a further update. Pharmacol Rev. 2022;74:340\u201372.","journal-title":"Pharmacol Rev"},{"key":"1526_CR40","doi-asserted-by":"publisher","first-page":"3196","DOI":"10.1152\/jn.1999.82.6.3196","volume":"82","author":"LV Lopes","year":"1999","unstructured":"Lopes LV, Cunha RA, Ribeiro JA. Cross talk between a(1) and a(2a) adenosine receptors in the hippocampus and cortex of young adult and old rats. J Neurophysiol. 1999;82:3196\u2013203.","journal-title":"J Neurophysiol"},{"key":"1526_CR41","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1111\/j.1460-9568.2011.07719.x","volume":"34","author":"AR Costenla","year":"2011","unstructured":"Costenla AR, Diogenes MJ, Canas PM, Rodrigues RJ, Nogueira C, Maroco J, et al. Enhanced role of adenosine a(2a) receptors in the modulation of ltp in the rat hippocampus upon ageing. Eur J Neurosci. 2011;34:12\u201321.","journal-title":"Eur J Neurosci"},{"key":"1526_CR42","doi-asserted-by":"publisher","first-page":"1877","DOI":"10.1016\/j.neurobiolaging.2008.01.003","volume":"30","author":"PM Canas","year":"2009","unstructured":"Canas PM, Duarte JM, Rodrigues RJ, Kofalvi A, Cunha RA. Modification upon aging of the density of presynaptic modulation systems in the hippocampus. Neurobiol Aging. 2009;30:1877\u201384.","journal-title":"Neurobiol Aging"},{"key":"1526_CR43","doi-asserted-by":"publisher","first-page":"11915","DOI":"10.1038\/ncomms11915","volume":"7","author":"S Viana da Silva","year":"2016","unstructured":"Viana da Silva S, Haberl MG, Zhang P, Bethge P, Lemos C, Goncalves N, et al. Early synaptic deficits in the app\/ps1 mouse model of alzheimer\u2019s disease involve neuronal adenosine a2a receptors. Nat Commun. 2016;7:11915.","journal-title":"Nat Commun"},{"key":"1526_CR44","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1038\/mp.2014.151","volume":"21","author":"C Laurent","year":"2016","unstructured":"Laurent C, Burnouf S, Ferry B, Batalha VL, Coelho JE, Baqi Y, et al. A2a adenosine receptor deletion is protective in a mouse model of tauopathy. Mol Psychiatry. 2016;21:97\u2013107.","journal-title":"Mol Psychiatry"},{"key":"1526_CR45","doi-asserted-by":"publisher","first-page":"104570","DOI":"10.1016\/j.nbd.2019.104570","volume":"132","author":"FQ Goncalves","year":"2019","unstructured":"Goncalves FQ, Lopes JP, Silva HB, Lemos C, Silva AC, Goncalves N, et al. Synaptic and memory dysfunction in a beta-amyloid model of early alzheimer\u2019s disease depends on increased formation of atp-derived extracellular adenosine. Neurobiol Dis. 2019;132:104570.","journal-title":"Neurobiol Dis"},{"key":"1526_CR46","doi-asserted-by":"publisher","first-page":"6702","DOI":"10.1073\/pnas.0802128105","volume":"105","author":"SK Michael","year":"2008","unstructured":"Michael SK, Surks HK, Wang Y, Zhu Y, Blanton R, Jamnongjit M, et al. High blood pressure arising from a defect in vascular function. Proc Natl Acad Sci U S A. 2008;105:6702\u20137.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1526_CR47","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1093\/cvr\/cvy023","volume":"114","author":"RM Touyz","year":"2018","unstructured":"Touyz RM, Alves-Lopes R, Rios FJ, Camargo LL, Anagnostopoulou A, Arner A, et al. Vascular smooth muscle contraction in hypertension. Cardiovasc Res. 2018;114:529\u201339.","journal-title":"Cardiovasc Res"},{"key":"1526_CR48","doi-asserted-by":"publisher","first-page":"1077302","DOI":"10.3389\/fragi.2022.1077302","volume":"3","author":"S Wang","year":"2022","unstructured":"Wang S, Tang C, Liu Y, Border JJ, Roman RJ, Fan F. Impact of impaired cerebral blood flow autoregulation on cognitive impairment. Front Aging. 2022;3:1077302.","journal-title":"Front Aging"},{"key":"1526_CR49","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.1007\/s11357-023-00773-x","volume":"45","author":"X Fang","year":"2023","unstructured":"Fang X, Tang C, Zhang H, Border JJ, Liu Y, Shin SM, et al. Longitudinal characterization of cerebral hemodynamics in the tgf344-ad rat model of alzheimer\u2019s disease. Geroscience. 2023;45:1471\u201390.","journal-title":"Geroscience"},{"key":"1526_CR50","doi-asserted-by":"publisher","first-page":"218","DOI":"10.3389\/fphys.2012.00218","volume":"3","author":"SB Cau","year":"2012","unstructured":"Cau SB, Carneiro FS, Tostes RC. Differential modulation of nitric oxide synthases in aging: therapeutic opportunities. Front Physiol. 2012;3:218.","journal-title":"Front Physiol"},{"key":"1526_CR51","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1161\/01.RES.83.3.279","volume":"83","author":"MR Cernadas","year":"1998","unstructured":"Cernadas MR, Sanchez de Miguel L, Garcia-Duran M, Gonzalez-Fernandez F, Millas I, Monton M, et al. Expression of constitutive and inducible nitric oxide synthases in the vascular wall of young and aging rats. Circ Res. 1998;83:279\u201386.","journal-title":"Circ Res"},{"key":"1526_CR52","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1161\/01.HYP.31.2.643","volume":"31","author":"TC Chou","year":"1998","unstructured":"Chou TC, Yen MH, Li CY, Ding YA. Alterations of nitric oxide synthase expression with aging and hypertension in rats. Hypertension. 1998;31:643\u20138.","journal-title":"Hypertension"},{"key":"1526_CR53","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1111\/j.1474-9726.2006.00232.x","volume":"5","author":"AR Smith","year":"2006","unstructured":"Smith AR, Visioli F, Frei B, Hagen TM. Age-related changes in endothelial nitric oxide synthase phosphorylation and nitric oxide dependent vasodilation: Evidence for a novel mechanism involving sphingomyelinase and ceramide-activated phosphatase 2a. Aging Cell. 2006;5:391\u2013400.","journal-title":"Aging Cell"},{"key":"1526_CR54","doi-asserted-by":"publisher","first-page":"5652","DOI":"10.3390\/molecules25235652","volume":"25","author":"CH Chou","year":"2020","unstructured":"Chou CH, Hsu KC, Lin TE, Yang CR. Anti-inflammatory and tau phosphorylation-inhibitory effects of eupatin. Molecules. 2020;25:5652.","journal-title":"Molecules."},{"key":"1526_CR55","first-page":"136","volume":"3","author":"WY Wang","year":"2015","unstructured":"Wang WY, Tan MS, Yu JT, Tan L. Role of pro-inflammatory cytokines released from microglia in alzheimer\u2019s disease. Ann Transl Med. 2015;3:136.","journal-title":"Ann Transl Med"},{"key":"1526_CR56","doi-asserted-by":"publisher","first-page":"763","DOI":"10.2174\/1566524043359908","volume":"4","author":"CV Suschek","year":"2004","unstructured":"Suschek CV, Schnorr O, Kolb-Bachofen V. The role of inos in chronic inflammatory processes in vivo: Is it damage-promoting, protective, or active at all? Curr Mol Med. 2004;4:763\u201375.","journal-title":"Curr Mol Med"},{"key":"1526_CR57","doi-asserted-by":"crossref","unstructured":"Lind M, Hayes A, Caprnda M, Petrovic D, Rodrigo L, Kruzliak P, et al. Inducible nitric oxide synthase: Good or bad?. Biomed Pharmacother= Biomed Pharmacother 2017;93:370\u2013375.","DOI":"10.1016\/j.biopha.2017.06.036"},{"key":"1526_CR58","first-page":"e21","volume":"52","author":"C Constantinides","year":"2011","unstructured":"Constantinides C, Mean R, Janssen BJ. Effects of isoflurane anesthesia on the cardiovascular function of the c57bl\/6 mouse. ILAR J. 2011;52:e21-31.","journal-title":"ILAR J"},{"key":"1526_CR59","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1097\/00000542-199809000-00024","volume":"89","author":"AL Loeb","year":"1998","unstructured":"Loeb AL, Raj NR, Longnecker DE. Cerebellar nitric oxide is increased during isoflurane anesthesia compared to halothane anesthesia: A microdialysis study in rats. Anesthesiology. 1998;89:723\u201330.","journal-title":"Anesthesiology"},{"key":"1526_CR60","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/S1052-3057(98)80003-7","volume":"7","author":"KW Park","year":"1998","unstructured":"Park KW, Dai HB, Lowenstein E, Stambler A, Sellke FW. Effect of isoflurane on the beta-adrenergic and endothelium-dependent relaxation of pig cerebral microvessels after cardiopulmonary bypass. J Stroke Cerebrovasc Dis. 1998;7:168\u201378.","journal-title":"J Stroke Cerebrovasc Dis"},{"key":"1526_CR61","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1007\/s00401-016-1662-x","volume":"133","author":"E Drummond","year":"2017","unstructured":"Drummond E, Wisniewski T. Alzheimer\u2019s disease: Experimental models and reality. Acta Neuropathol. 2017;133:155\u201375.","journal-title":"Acta Neuropathol"},{"key":"1526_CR62","doi-asserted-by":"publisher","first-page":"975","DOI":"10.3233\/JAD-160612","volume":"57","author":"R Rajmohan","year":"2017","unstructured":"Rajmohan R, Reddy PH. Amyloid-beta and phosphorylated tau accumulations cause abnormalities at synapses of alzheimer\u2019s disease neurons. J Alzheimers Dis. 2017;57:975\u201399.","journal-title":"J Alzheimers Dis"},{"key":"1526_CR63","doi-asserted-by":"publisher","first-page":"282","DOI":"10.3389\/fnagi.2017.00282","volume":"9","author":"F Zhang","year":"2017","unstructured":"Zhang F, Zhong R, Li S, Fu Z, Cheng C, Cai H, et al. Acute hypoxia induced an imbalanced m1\/m2 activation of microglia through nf-kappab signaling in alzheimer\u2019s disease mice and wild-type littermates. Front Aging Neurosci. 2017;9:282.","journal-title":"Front Aging Neurosci"},{"key":"1526_CR64","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1007\/s12079-021-00663-x","volume":"16","author":"AFO Justo","year":"2022","unstructured":"Justo AFO, Suemoto CK. The modulation of neuroinflammation by inducible nitric oxide synthase. J Cell Commun Signal. 2022;16:155\u20138.","journal-title":"J Cell Commun Signal"},{"key":"1526_CR65","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/nrc3409","volume":"13","author":"Y Yang","year":"2013","unstructured":"Yang Y, Bedford MT. Protein arginine methyltransferases and cancer. Nat Rev Cancer. 2013;13:37\u201350.","journal-title":"Nat Rev Cancer"},{"key":"1526_CR66","doi-asserted-by":"publisher","first-page":"1716","DOI":"10.1007\/s12035-019-01850-z","volume":"57","author":"ESA Couto","year":"2020","unstructured":"Couto ESA, Wu CY, Citadin CT, Clemons GA, Possoit HE, Grames MS, et al. Protein arginine methyltransferases in cardiovascular and neuronal function. Mol Neurobiol. 2020;57:1716\u201332.","journal-title":"Mol Neurobiol"},{"key":"1526_CR67","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1111\/nyas.14798","volume":"1514","author":"WT Kuo","year":"2022","unstructured":"Kuo WT, Odenwald MA, Turner JR, Zuo L. Tight junction proteins occludin and zo-1 as regulators of epithelial proliferation and survival. Ann N Y Acad Sci. 2022;1514:21\u201333.","journal-title":"Ann N Y Acad Sci"},{"key":"1526_CR68","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1111\/j.1749-6632.2009.04440.x","volume":"1165","author":"AS Fanning","year":"2009","unstructured":"Fanning AS, Anderson JM. Zonula occludens-1 and -2 are cytosolic scaffolds that regulate the assembly of cellular junctions. Ann N Y Acad Sci. 2009;1165:113\u201320.","journal-title":"Ann N Y Acad Sci"},{"key":"1526_CR69","doi-asserted-by":"publisher","first-page":"108119","DOI":"10.1016\/j.pharmthera.2022.108119","volume":"234","author":"G Nehra","year":"2022","unstructured":"Nehra G, Bauer B, Hartz AMS. Blood-brain barrier leakage in alzheimer\u2019s disease: From discovery to clinical relevance. Pharmacol Ther. 2022;234:108119.","journal-title":"Pharmacol Ther"},{"key":"1526_CR70","doi-asserted-by":"publisher","first-page":"1102809","DOI":"10.3389\/fnagi.2023.1102809","volume":"15","author":"JA Sousa","year":"2023","unstructured":"Sousa JA, Bernardes C, Bernardo-Castro S, Lino M, Albino I, Ferreira L, et al. Reconsidering the role of blood-brain barrier in alzheimer\u2019s disease: From delivery to target. Front Aging Neurosci. 2023;15:1102809.","journal-title":"Front Aging Neurosci"},{"key":"1526_CR71","doi-asserted-by":"publisher","first-page":"e23789","DOI":"10.1371\/journal.pone.0023789","volume":"6","author":"KE Biron","year":"2011","unstructured":"Biron KE, Dickstein DL, Gopaul R, Jefferies WA. Amyloid triggers extensive cerebral angiogenesis causing blood brain barrier permeability and hypervascularity in alzheimer\u2019s disease. PLoS ONE. 2011;6:e23789.","journal-title":"PLoS ONE"},{"key":"1526_CR72","doi-asserted-by":"publisher","first-page":"14729","DOI":"10.3390\/ijms232314729","volume":"23","author":"MV Kondashevskaya","year":"2022","unstructured":"Kondashevskaya MV, Downey HF, Tseilikman VE, Alexandrin VV, Artem\u2019yeva KA, Aleksankina VV, et al. Cerebral blood flow in predator stress-resilient and -susceptible rats and mechanisms of resilience. Int J Mol Sci. 2022;23:14729.","journal-title":"Int J Mol Sci"},{"key":"1526_CR73","first-page":"e52434","volume":"38","author":"ML Seibenhener","year":"2015","unstructured":"Seibenhener ML, Wooten MC. Use of the open field maze to measure locomotor and anxiety-like behavior in mice. J Vis Exp. 2015;38:e52434.","journal-title":"J Vis Exp"},{"key":"1526_CR74","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1519\/JPT.0000000000000020","volume":"38","author":"LZ Gras","year":"2015","unstructured":"Gras LZ, Kanaan SF, McDowd JM, Colgrove YM, Burns J, Pohl PS. Balance and gait of adults with very mild alzheimer disease. J Geriatr Phys Ther. 2015;38:1\u20137.","journal-title":"J Geriatr Phys Ther"},{"key":"1526_CR75","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.nbd.2016.07.007","volume":"107","author":"E Zenaro","year":"2017","unstructured":"Zenaro E, Piacentino G, Constantin G. The blood-brain barrier in alzheimer\u2019s disease. Neurobiol Dis. 2017;107:41\u201356.","journal-title":"Neurobiol Dis"},{"key":"1526_CR76","doi-asserted-by":"publisher","first-page":"21177","DOI":"10.1038\/s41598-021-00402-7","volume":"11","author":"R d'Isa","year":"2021","unstructured":"d\u2019Isa R, Comi G, Leocani L. Apparatus design and behavioural testing protocol for the evaluation of spatial working memory in mice through the spontaneous alternation t-maze. Sci Rep. 2021;11:21177.","journal-title":"Sci Rep"},{"key":"1526_CR77","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.lmot.2017.03.009","volume":"61","author":"SM Thompson","year":"2018","unstructured":"Thompson SM, Berkowitz LE, Clark BJ. Behavioral and neural subsystems of rodent exploration. Learn Motiv. 2018;61:3\u201315.","journal-title":"Learn Motiv"},{"key":"1526_CR78","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1016\/j.neubiorev.2006.03.006","volume":"30","author":"MP Leussis","year":"2006","unstructured":"Leussis MP, Bolivar VJ. Habituation in rodents: A review of behavior, neurobiology, and genetics. Neurosci Biobehav Rev. 2006;30:1045\u201364.","journal-title":"Neurosci Biobehav Rev"},{"key":"1526_CR79","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/nprot.2006.2","volume":"1","author":"RM Deacon","year":"2006","unstructured":"Deacon RM, Rawlins JN. T-maze alternation in the rodent. Nat Protoc. 2006;1:7\u201312.","journal-title":"Nat Protoc"},{"key":"1526_CR80","doi-asserted-by":"publisher","first-page":"85","DOI":"10.3233\/JAD-2009-0920","volume":"16","author":"MH Eskelinen","year":"2009","unstructured":"Eskelinen MH, Ngandu T, Tuomilehto J, Soininen H, Kivipelto M. Midlife coffee and tea drinking and the risk of late-life dementia: A population-based caide study. J Alzheimers Dis. 2009;16:85\u201391.","journal-title":"J Alzheimers Dis"},{"key":"1526_CR81","doi-asserted-by":"publisher","first-page":"559","DOI":"10.3233\/JAD-2012-111781","volume":"30","author":"C Cao","year":"2012","unstructured":"Cao C, Loewenstein DA, Lin X, Zhang C, Wang L, Duara R, et al. High blood caffeine levels in mci linked to lack of progression to dementia. J Alzheimers Dis. 2012;30:559\u201372.","journal-title":"J Alzheimers Dis"},{"key":"1526_CR82","doi-asserted-by":"publisher","first-page":"2079","DOI":"10.1016\/j.neurobiolaging.2014.03.027","volume":"35","author":"C Laurent","year":"2014","unstructured":"Laurent C, Eddarkaoui S, Derisbourg M, Leboucher A, Demeyer D, Carrier S, et al. Beneficial effects of caffeine in a transgenic model of alzheimer\u2019s disease-like tau pathology. Neurobiol Aging. 2014;35:2079\u201390.","journal-title":"Neurobiol Aging"},{"key":"1526_CR83","doi-asserted-by":"publisher","first-page":"3831","DOI":"10.1111\/bph.13180","volume":"172","author":"N Pagnussat","year":"2015","unstructured":"Pagnussat N, Almeida AS, Marques DM, Nunes F, Chenet GC, Botton PH, et al. Adenosine a(2a) receptors are necessary and sufficient to trigger memory impairment in adult mice. Br J Pharmacol. 2015;172:3831\u201345.","journal-title":"Br J Pharmacol"},{"key":"1526_CR84","doi-asserted-by":"publisher","first-page":"2344","DOI":"10.3390\/cells10092344","volume":"10","author":"S Gessi","year":"2021","unstructured":"Gessi S, Poloni TE, Negro G, Varani K, Pasquini S, Vincenzi F, et al. A(2a) adenosine receptor as a potential biomarker and a possible therapeutic target in alzheimer\u2019s disease. Cells. 2021;10:2344.","journal-title":"Cells"},{"key":"1526_CR85","doi-asserted-by":"publisher","first-page":"109379","DOI":"10.1016\/j.neuropharm.2022.109379","volume":"226","author":"A Launay","year":"2023","unstructured":"Launay A, Nebie O, VijayaShankara J, Lebouvier T, Buee L, Faivre E, et al. The role of adenosine a(2a) receptors in alzheimer\u2019s disease and tauopathies. Neuropharmacology. 2023;226:109379.","journal-title":"Neuropharmacology"},{"key":"1526_CR86","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1007\/s11302-020-09694-2","volume":"16","author":"JF Chen","year":"2020","unstructured":"Chen JF, Cunha RA. The belated us fda approval of the adenosine a(2a) receptor antagonist istradefylline for treatment of parkinson\u2019s disease. Purinergic Signal. 2020;16:167\u201374.","journal-title":"Purinergic Signal"}],"container-title":["GeroScience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11357-025-01526-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11357-025-01526-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11357-025-01526-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,21]],"date-time":"2025-06-21T13:02:24Z","timestamp":1750510944000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11357-025-01526-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,22]]},"references-count":86,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["1526"],"URL":"https:\/\/doi.org\/10.1007\/s11357-025-01526-8","relation":{},"ISSN":["2509-2723"],"issn-type":[{"value":"2509-2723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,22]]},"assertion":[{"value":"20 November 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 January 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 January 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the Institutional Animal Care and Use Committee at the University of Texas Health Science Center (UTHealth) at Houston, TX (protocol AWC-24\u20130006).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"This research did not involve human participants.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"All authors agreed with the content of this research and approved the publication of this work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"Authors MSBU, JZM, GAC, CTC, JL, DJS, LHM, and VT have no competing interests to declare. Author HWL is a consultant for Neurelis Inc, however none of the work presented was supported by Neurelis Inc.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}