{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:45:55Z","timestamp":1786977955546,"version":"build-2736575974"},"reference-count":65,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T00:00:00Z","timestamp":1661731200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Alzheimer's disease (AD) is the leading cause of mortality, disability, and long\u2010term care burden in the United States, with women comprising the majority of AD diagnoses. While AD\u2010related dementia is associated with tau and amyloid beta accumulation, concurrent derangements in cerebral blood flow have been observed alongside these proteinopathies in humans and rodent models. The homeostatic production of nitric oxide synthases (NOS) becomes uncoupled in AD which leads to decreased NO\u2010mediated vasodilation and oxidative stress via the production of peroxynitrite (ONOO\u2212\u2219) superoxide species. Here, we investigate the role of the novel protein arginine methyltransferase 4 (PRMT4) enzyme function and its downstream product asymmetric dimethyl arginine (ADMA) as it relates to NOS dysregulation and cerebral blood flow in AD. ADMA (type\u20101 PRMT product) has been shown to bind NOS as a noncanonic ligand causing enzymatic dysfunction. Our results from RT\u2010qPCR and protein analyses suggest that aged (9\u221212 months) female mice bearing tau\u2010 and amyloid beta\u2010producing transgenic mutations (3xTg\u2010AD) express higher levels of PRMT4 in the hippocampus when compared to age\u2010 and sex\u2010matched C57BL6\/J mice. In addition, we performed studies to quantify the expression and activity of different NOS isoforms. Furthermore, laser speckle contrast imaging analysis was indicative that 3xTg\u2010AD mice have dysfunctional NOS activity, resulting in reduced production of NO metabolites, enhanced production of free\u2010radical ONOO\u2212, and decreased cerebral blood flow. Notably, the aforementioned phenomena can be reversed via pharmacologic PRMT4 inhibition. Together, these findings implicate the potential importance of PRMT4 signaling in the pathogenesis of Alzheimer's\u2010related cerebrovascular derangement.<\/jats:p>","DOI":"10.1002\/jcp.30858","type":"journal-article","created":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T12:35:33Z","timestamp":1661776533000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Protein arginine methyltransferase 4 modulates nitric oxide synthase uncoupling and cerebral blood flow in Alzheimer's disease"],"prefix":"10.1002","volume":"239","author":[{"given":"Garrett A.","family":"Clemons","sequence":"first","affiliation":[{"name":"Department of Cellular Biology &amp; Anatomy Louisiana State University Health Sciences Center Shreveport Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre Couto e","family":"Silva","sequence":"additional","affiliation":[{"name":"Oregon Health and Science University Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina H.","family":"Acosta","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology &amp; Anatomy Louisiana State University Health Sciences Center Shreveport Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana Sayuri Berto","family":"Udo","sequence":"additional","affiliation":[{"name":"Department of Neurology Louisiana State University Health Sciences Center Shreveport Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vesna","family":"Tesic","sequence":"additional","affiliation":[{"name":"Department of Neurology Louisiana State University Health Sciences Center Shreveport Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krista M.","family":"Rodgers","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology &amp; Anatomy Louisiana State University Health Sciences Center Shreveport Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celeste Yin\u2010Chieh","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Neurology Louisiana State University Health Sciences Center Shreveport Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiane T.","family":"Citadin","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology &amp; Anatomy Louisiana State University Health Sciences Center Shreveport Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reggie Hui\u2010Chao","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurology Louisiana State University Health Sciences Center Shreveport Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jake T.","family":"Neumann","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences West Virginia School of Osteopathic Medicine Lewisburg West Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1900-2933","authenticated-orcid":false,"given":"Shailaja","family":"Allani","sequence":"additional","affiliation":[{"name":"Center for Molecular Biology and Biotechnology Florida Atlantic University Jupiter Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard","family":"Prentice","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Charles E. Schmidt College of Medicine Florida Atlantic University Boca Raton Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanguang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology Louisiana State University Health Sciences Center Shreveport Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1010-5423","authenticated-orcid":false,"given":"Hung Wen","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology &amp; Anatomy Louisiana State University Health Sciences Center Shreveport Louisiana USA"},{"name":"Department of Neurology Louisiana State University Health Sciences Center Shreveport Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,8,29]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/138.10.1902"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1042\/0264-6021:3570593"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jcbfm.9600570"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/0271678\/18822474"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12334"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2018.00270"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2016.11.003"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1177\/0271678\/19873658"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.niox.2019.08.001"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2020.08.020"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.678282"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nrl.2012.01.001"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.619211"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-006-0592-5"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/1746-1596-8-129"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201901318.R"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.117.09742"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1097\/00002093-200000001-00012"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0197-4580(00)00111-1"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jcbfm.9600057"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00238.2016"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi702377a"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1177\/1039856218762308"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.525345"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.niox.2019.04.007"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1006\/nimg.1998.0376"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0155-x"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2019.06.009"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.niox.2019.03.006"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.22871"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.2174\/1567205018666210820124135"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.08.115"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0002-9149(96)00182-8"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M809547200"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aaf7329"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-190474"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2006.06.038"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2002.11.008"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22136662"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2019.11.015"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.24883"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-020-01108-z"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav9518"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0896-6273(03)00434-3"},{"key":"e_1_2_10_46_1","doi-asserted-by":"crossref","unstructured":"Onwuli D. 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