{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T18:57:29Z","timestamp":1789844249706,"version":"4.0.1"},"reference-count":93,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,5,3]],"date-time":"2025-05-03T00:00:00Z","timestamp":1746230400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["R01AG075583"],"award-info":[{"award-number":["R01AG075583"]}]},{"name":"National Institute of Health","award":["R01NS133250"],"award-info":[{"award-number":["R01NS133250"]}]},{"name":"National Institute of Health","award":["R01AG039621"],"award-info":[{"award-number":["R01AG039621"]}]},{"name":"National Institute of Health","award":["PHD58I0010"],"award-info":[{"award-number":["PHD58I0010"]}]},{"name":"Research and Researchers for Industry Grant","award":["R01AG075583"],"award-info":[{"award-number":["R01AG075583"]}]},{"name":"Research and Researchers for Industry Grant","award":["R01NS133250"],"award-info":[{"award-number":["R01NS133250"]}]},{"name":"Research and Researchers for Industry Grant","award":["R01AG039621"],"award-info":[{"award-number":["R01AG039621"]}]},{"name":"Research and Researchers for Industry Grant","award":["PHD58I0010"],"award-info":[{"award-number":["PHD58I0010"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is characterized by amyloid-beta (A\u03b2) pathology and is closely linked to oxidative stress, which contributes to blood\u2013brain barrier leakage, renal dysfunction, and cognitive decline. We investigated the effects of N-acetyl cysteine (NAC), an FDA-approved antioxidant, on oxidative stress, brain A\u03b2 levels, barrier leakage, renal function, and cognition in 5xFAD mice. Eight-week-old 5xFAD mice were fed a rodent diet supplemented with 600 mg\/kgDiet NAC for 4 weeks; wild-type (WT) mice and control 5xFAD mice were fed a regular rodent diet. We detected elevated brain and renal 4-hydroxynonenal(4-HNE) levels, reduced creatinine clearance, and increased plasma S100\u03b2 levels in untreated 5xFAD mice compared to WT controls. Untreated 5xFAD mice also had higher capillary leakage, reduced P-gp activity, and impaired cognition compared to WT. NAC treatment of 5xFAD mice reduced brain A\u03b240 levels, normalized 4-HNE levels to control levels, improved creatinine clearance, decreased capillary leakage, and lowered S100\u03b2 plasma levels. NAC improved cognitive performance in 5xFAD mice, as shown by Y-maze. Our findings indicate that A\u03b2-induced oxidative stress contributes to barrier dysfunction, renal impairment, and cognitive deficits in 5xFAD mice. Notably, NAC treatment mitigates these effects, suggesting its potential as an adjunct therapy for AD and other A\u03b2-related pathologies by reducing oxidative stress.<\/jats:p>","DOI":"10.3390\/ijms26094352","type":"journal-article","created":{"date-parts":[[2025,5,4]],"date-time":"2025-05-04T20:10:27Z","timestamp":1746389427000},"page":"4352","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["N-Acetylcysteine Attenuates A\u03b2-Mediated Oxidative Stress, Blood\u2013Brain Barrier Leakage, and Renal Dysfunction in 5xFAD Mice"],"prefix":"10.3390","volume":"26","author":[{"given":"Atcharaporn","family":"Ontawong","sequence":"first","affiliation":[{"name":"Sanders-Brown Center on Aging, College of Medicine, University of Kentucky, Lexington, KY 40536, USA"},{"name":"Division of Physiology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4376-5313","authenticated-orcid":false,"given":"Geetika","family":"Nehra","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, College of Medicine, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2364-9649","authenticated-orcid":false,"given":"Bryan J.","family":"Maloney","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, College of Medicine, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5537-1023","authenticated-orcid":false,"given":"Chutima S.","family":"Vaddhanaphuti","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3867-2251","authenticated-orcid":false,"given":"Bj\u00f6rn","family":"Bauer","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, College of Medicine, University of Kentucky, Lexington, KY 40536, USA"},{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anika M. S.","family":"Hartz","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, College of Medicine, University of Kentucky, Lexington, KY 40536, USA"},{"name":"Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer\u2019s Disease: Causes and Treatment. Molecules, 25.","DOI":"10.3390\/molecules25245789"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e158453","DOI":"10.1172\/JCI158453","article-title":"Biological aging processes underlying cognitive decline and neurodegenerative disease","volume":"132","author":"Gonzales","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"105219","DOI":"10.1016\/j.archger.2023.105219","article-title":"Trajectories of quality of life and cognition in different multimorbidity patterns: Evidence from SHARE","volume":"117","author":"Li","year":"2024","journal-title":"Arch. Gerontol. Geriatr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2272","DOI":"10.1007\/s11606-023-08031-8","article-title":"Healthcare Utilization and Mortality After Hospice Live Discharge Among Medicare Patients With and Without Alzheimer\u2019s Disease and Related Dementias","volume":"38","author":"Zhang","year":"2023","journal-title":"J. Gen. Intern. Med."},{"key":"ref_5","first-page":"881","article-title":"Molecular mechanisms of oxidative stress in aging: Free radicals, aging, antioxidants and disease","volume":"Volume 30","author":"Sen","year":"1999","journal-title":"Handbook of Oxidants and Antioxidants in Exercise"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"855","DOI":"10.2147\/NDT.S3739","article-title":"Brain ischemia and ischemic blood\u2013brain barrier as etiological factors in sporadic Alzheimer\u2019s disease","volume":"4","author":"Pluta","year":"2008","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Yu, S., Zuo, L., Wang, F., Chen, Z., Hu, Y., Wang, Y., Wang, X., and Zhang, W. (2014). Potential biomarkers relating pathological proteins, neuroinflammatory factors and free radicals in PD patients with cognitive impairment: A cross-sectional study. BMC Neurol., 14.","DOI":"10.1186\/1471-2377-14-113"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/S0891-5849(96)00629-6","article-title":"Oxidative stress hypothesis in Alzheimer\u2019s disease","volume":"23","author":"Markesbery","year":"1997","journal-title":"Free Radic. Biol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1080\/1071576021000049890","article-title":"Amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity: Implications for neurodegeneration in Alzheimer\u2019s disease brain. A review","volume":"36","author":"Butterfield","year":"2002","journal-title":"Free Radic. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1089\/ars.2011.3895","article-title":"Amyloid Beta induces oxidative stress-mediated blood-brain barrier changes in capillary amyloid angiopathy","volume":"15","author":"Carrano","year":"2011","journal-title":"Antioxid. Redox Signal"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1159\/000334916","article-title":"Neuroinflammation and blood-brain barrier changes in capillary amyloid angiopathy","volume":"10","author":"Carrano","year":"2012","journal-title":"Neurodegener. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"S35","DOI":"10.3233\/JAD-220909","article-title":"Association of Dietary and Supplement Intake of Antioxidants with Risk of Dementia: A Meta-Analysis of Cohort Studies","volume":"99","author":"Zhao","year":"2024","journal-title":"J. Alzheimers Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e1083","DOI":"10.1038\/cddis.2014.26","article-title":"High-dose of vitamin C supplementation reduces amyloid plaque burden and ameliorates pathological changes in the brain of 5XFAD mice","volume":"5","author":"Kook","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1001\/archneur.61.1.82","article-title":"Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: The Cache County Study","volume":"61","author":"Zandi","year":"2004","journal-title":"Arch. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3230","DOI":"10.1001\/jama.287.24.3230","article-title":"Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study","volume":"287","author":"Morris","year":"2002","journal-title":"JAMA"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zhao, R., Han, X., Zhang, H., Liu, J., Zhang, M., Zhao, W., Jiang, S., Li, R., Cai, H., and You, H. (2022). Association of vitamin E intake in diet and supplements with risk of dementia: A meta-analysis. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.955878"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/0007-0971(85)90046-4","article-title":"Effect of oral N-acetylcysteine on mucus clearance","volume":"79","author":"Millar","year":"1985","journal-title":"Br. J. Dis. Chest"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9949453","DOI":"10.1155\/2021\/9949453","article-title":"N-Acetylcysteine: A Review of Clinical Usefulness (an Old Drug with New Tricks)","volume":"2021","author":"Schwalfenberg","year":"2021","journal-title":"J. Nutr. Metab."},{"key":"ref_19","first-page":"11","article-title":"A Review on Various Uses of N-Acetyl Cysteine","volume":"19","author":"Mokhtari","year":"2017","journal-title":"Cell J."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ten\u00f3rio, M.C.D.S., Graciliano, N.G., Moura, F.A., Oliveira, A.C.M., and Goulart, M.O.F. (2021). N-Acetylcysteine (NAC): Impacts on Human Health. Antioxidants, 10.","DOI":"10.3390\/antiox10060967"},{"key":"ref_21","first-page":"201","article-title":"Evaluation of the Neuroprotective Potential of N-Acetylcysteine for Prevention and Treatment of Cognitive Aging and Dementia","volume":"4","author":"Hara","year":"2017","journal-title":"J. Prev. Alzheimers Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"591","DOI":"10.3233\/JAD-150057","article-title":"A Nutritional Formulation for Cognitive Performance in Mild Cognitive Impairment: A Placebo-Controlled Trial with an Open-Label Extension","volume":"48","author":"Remington","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_23","unstructured":"(2025, January 22). NCT00597376. Study of the Effects of Cerefolin NAC on Inflammation Blood Markers in Older Individuals with Memory Complaints, Available online: https:\/\/clinicaltrials.gov\/study\/NCT00597376."},{"key":"ref_24","unstructured":"(2025, January 22). NCT01320527. A Clinical Trial of a Vitamin\/Nutriceutical Formulation for Alzheimer\u2019s Disease, Available online: https:\/\/clinicaltrials.gov\/study\/NCT01320527."},{"key":"ref_25","unstructured":"(2025, January 22). NCT01370954 NAC-003, P.L.U.S. Program (Progress Through Learning Understanding & Support), Available online: https:\/\/clinicaltrials.gov\/study\/NCT01370954."},{"key":"ref_26","unstructured":"(2025, January 22). NCT01745198. Effect of Cerefolin\u00ae\/CerefolinNAC\u00ae on Biomarker Measurements, Available online: https:\/\/clinicaltrials.gov\/study\/NCT01745198."},{"key":"ref_27","doi-asserted-by":"crossref","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":"ref_28","doi-asserted-by":"crossref","unstructured":"Devi, L., and Ohno, M. (2010). Phospho-eIF2\u03b1 level is important for determining abilities of BACE1 reduction to rescue cholinergic neurodegeneration and memory defects in 5XFAD mice. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012974"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"196.e29","DOI":"10.1016\/j.neurobiolaging.2010.05.027","article-title":"Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal A\u03b2 aggregation in the 5XFAD mouse model of Alzheimer\u2019s disease","volume":"33","author":"Jawhar","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"12137","DOI":"10.1523\/JNEUROSCI.0705-15.2015","article-title":"Neuronal-Targeted TFEB Accelerates Lysosomal Degradation of APP, Reducing A\u03b2 Generation and Amyloid Plaque Pathogenesis","volume":"35","author":"Xiao","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","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":"Bracko","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1017\/S0317167100013949","article-title":"Early-onset familial Alzheimer\u2019s disease (EOFAD)","volume":"39","author":"Wu","year":"2012","journal-title":"Can. J. Neurol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","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":"ref_34","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nrneurol.2015.119","article-title":"Clearance systems in the brain-implications for Alzheimer disease","volume":"11","author":"Carare","year":"2015","journal-title":"Nat. Rev. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1007\/s00401-015-1477-1","article-title":"Physiological amyloid-beta clearance in the periphery and its therapeutic potential for Alzheimer\u2019s disease","volume":"130","author":"Xiang","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6074","DOI":"10.1038\/s41380-021-01073-6","article-title":"Physiological clearance of amyloid-beta by the kidney and its therapeutic potential for Alzheimer\u2019s disease","volume":"26","author":"Tian","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s12035-014-8854-y","article-title":"Association Between Serum Amyloid-Beta and Renal Functions: Implications for Roles of Kidney in Amyloid-Beta Clearance","volume":"52","author":"Liu","year":"2015","journal-title":"Mol. Neurobiol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Berger, I., Wu, S., Masson, P., Kelly, P.J., Duthie, F.A., Whiteley, W., Parker, D., Gillespie, D., and Webster, A.C. (2016). Cognition in chronic kidney disease: A systematic review and meta-analysis. BMC Med., 14.","DOI":"10.1186\/s12916-016-0745-9"},{"key":"ref_39","unstructured":"H Walker, K., Hall, W.D., and Hurst, W. (1990). Aminotransferases. Clinical Methods: The History, Physical, and Laboratory Examinations, Butterworth Publishers, a division of Reed Publishing. [3rd ed.]. Chapter 99."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"925","DOI":"10.7150\/ijms.8951","article-title":"Alanine aminotransferase-old biomarker and new concept: A review","volume":"11","author":"Liu","year":"2014","journal-title":"Int. J. Med. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s13195-022-01016-5","article-title":"Longitudinal evaluation of neuroinflammation and oxidative stress in a mouse model of Alzheimer disease using positron emission tomography","volume":"14","author":"Rejc","year":"2022","journal-title":"Alzheimers Res. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Wendt, S., Johnson, S., Weilinger, N.L., Groten, C., Sorrentino, S., Frew, J., Yang, L., Choi, H.B., Nygaard, H.B., and MacVicar, B.A. (2022). Simultaneous imaging of redox states in dystrophic neurites and microglia at A\u03b2 plaques indicate lysosome accumulation not microglia correlate with increased oxidative stress. Redox Biol., 56.","DOI":"10.1016\/j.redox.2022.102448"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6501046","DOI":"10.1155\/2017\/6501046","article-title":"Measurement and Clinical Significance of Biomarkers of Oxidative Stress in Humans","volume":"2017","author":"Marrocco","year":"2017","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"327","DOI":"10.4062\/biomolther.2019.046","article-title":"Theracurmin Ameliorates Cognitive Dysfunctions in 5XFAD Mice by Improving Synaptic Function and Mitigating Oxidative Stress","volume":"27","author":"Kim","year":"2019","journal-title":"Biomol. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Tamagno, E., Guglielmotto, M., Vasciaveo, V., and Tabaton, M. (2021). Oxidative Stress and Beta Amyloid in Alzheimer\u2019s Disease. Which Comes First: The Chicken or the Egg?. Antioxidants, 10.","DOI":"10.3390\/antiox10091479"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Kim, J.H., Lim, D.K., Suh, Y.H., and Chang, K.A. (2021). Long-Term Treatment of Cuban Policosanol Attenuates Abnormal Oxidative Stress and Inflammatory Response via Amyloid Plaques Reduction in 5xFAD Mice. Antioxidants, 10.","DOI":"10.3390\/antiox10081321"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Shin, S.W., Kim, D.H., Jeon, W.K., and Han, J.S. (2020). 4-Hydroxynonenal Immunoreactivity Is Increased in the Frontal Cortex of 5XFAD Transgenic Mice. Biomedicines, 8.","DOI":"10.3390\/biomedicines8090326"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.foodchem.2017.02.127","article-title":"Measurement of antioxidant activity with the thiobarbituric acid reactive substances assay","volume":"230","author":"Ghani","year":"2017","journal-title":"Food Chem."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Peng, A., Gao, Y., Zhuang, X., Lin, Y., He, W., Wang, Y., Chen, W., Chen, T., Huang, X., and Yang, R. (2019). Bazhu Decoction, a Traditional Chinese Medical Formula, Ameliorates Cognitive Deficits in the 5xFAD Mouse Model of Alzheimer\u2019s Disease. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.01391"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Tang, J.J., Huang, L.F., Deng, J.L., Wang, Y.M., Guo, C., Peng, X.N., Liu, Z., and Gao, J.M. (2022). Cognitive enhancement and neuroprotective effects of OABL, a sesquiterpene lactone in 5xFAD Alzheimer\u2019s disease mice model. Redox Biol., 50.","DOI":"10.1016\/j.redox.2022.102229"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4225","DOI":"10.1529\/biophysj.107.112565","article-title":"Effect of lipid peroxidation on the properties of lipid bilayers: A molecular dynamics study","volume":"93","author":"Xu","year":"2007","journal-title":"Biophys. J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1089\/ars.2011.3923","article-title":"Oxidative stress and blood-brain barrier dysfunction under particular consideration of matrix metalloproteinases","volume":"15","author":"Lehner","year":"2011","journal-title":"Antioxid. Redox Signal"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Lee, H.J., Jeong, H.R., Park, J.H., and Hoe, H.S. (2021). Idebenone Decreases A\u03b2 Pathology by Modulating RAGE\/Caspase-3 Signaling and the A\u03b2 Degradation Enzyme NEP in a Mouse Model of AD. Biology, 10.","DOI":"10.3390\/biology10090938"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1021\/acschemneuro.7b00101","article-title":"Crocus sativus Extract Tightens the Blood-Brain Barrier, Reduces Amyloid \u03b2 Load and Related Toxicity in 5XFAD Mice","volume":"8","author":"Batarseh","year":"2017","journal-title":"ACS Chem. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1159\/000445171","article-title":"Non-Transgenic Mouse Models of Kidney Disease","volume":"133","author":"Rabe","year":"2016","journal-title":"Nephron"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"F674","DOI":"10.1152\/ajprenal.00196.2020","article-title":"C57BL\/6 mice require a higher dose of cisplatin to induce renal fibrosis and CCL2 correlates with cisplatin-induced kidney injury","volume":"319","author":"Sears","year":"2020","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_57","first-page":"10972","article-title":"Chronic kidney disease causes blood-brain barrier breakdown via urea-activated matrix metalloproteinase-2 and insolubility of tau protein","volume":"15","author":"Matsuki","year":"2023","journal-title":"Aging"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.exger.2016.11.012","article-title":"Chronic kidney disease accelerates cognitive impairment in a mouse model of Alzheimer\u2019s disease, through angiotensin II","volume":"87","author":"Nakagawa","year":"2017","journal-title":"Exp. Gerontol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Manna, J., Dunbar, G.L., and Maiti, P. (2021). Curcugreen Treatment Prevented Splenomegaly and Other Peripheral Organ Abnormalities in 3xTg and 5xFAD Mouse Models of Alzheimer\u2019s Disease. Antioxidants, 10.","DOI":"10.3390\/antiox10060899"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1097\/00002093-200207000-00009","article-title":"Serum creatinine levels correlate with plasma amyloid Beta protein","volume":"16","author":"Arvanitakis","year":"2002","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.bbacli.2017.06.001","article-title":"Abnormal amyloid \u03b2","volume":"8","author":"Vinothkumar","year":"2017","journal-title":"BBA Clin."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2988","DOI":"10.1016\/j.ekir.2024.07.021","article-title":"Increased Blood-Brain Barrier Permeability and Cognitive Impairment in Patients With ESKD","volume":"9","author":"Bobot","year":"2024","journal-title":"Kidney Int. Rep."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1096\/fj.07-9574LSF","article-title":"Dose translation from animal to human studies revisited","volume":"22","author":"Nihal","year":"2008","journal-title":"FASEB J."},{"key":"ref_64","first-page":"2619","article-title":"Intravenous administration of stable-labeled N-acetylcysteine demonstrates an indirect mechanism for boosting glutathione and improving redox status","volume":"104","author":"Zhou","year":"2015","journal-title":"Pharmacokin Pharmacod Drug Transport Metab."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/BF00606662","article-title":"Pharmacokinetics of N-acetylcysteine in man","volume":"31","author":"Paulsen","year":"1986","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"427318","DOI":"10.1155\/2014\/427318","article-title":"Oxidative stress in Alzheimer\u2019s disease: Why did antioxidant therapy fail?","volume":"2014","author":"Persson","year":"2014","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Gualtieri, P., Frank, G., Cianci, R., Ciancarella, L., Romano, L., Ortoman, M., Bigioni, G., Nicoletti, F., Falco, M.I., and La Placa, G. (2025). Exploring the Efficacy and Safety of Nutritional Supplements in Alzheimer\u2019s Disease. Nutrients, 17.","DOI":"10.3390\/nu17050922"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Bowers, Z., Maiti, P., Bourcier, A., Morse, J., Jenrow, K., Rossignol, J., and Dunbar, G.L. (2021). Tart Cherry Extract and Omega Fatty Acids Reduce Behavioral Deficits, Gliosis, and Amyloid-Beta Deposition in the 5xFAD Mouse Model of Alzheimer\u2019s Disease. Brain Sci., 11.","DOI":"10.3390\/brainsci11111423"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Ji, Y.J., Kim, S., Kim, J.J., Jang, G.Y., Moon, M., and Kim, H.D. (2021). Crude Saponin from Platycodon grandiflorum Attenuates A\u03b2-Induced Neurotoxicity via Antioxidant, Anti-Inflammatory and Anti-Apoptotic Signaling Pathways. Antioxidants, 10.","DOI":"10.3390\/antiox10121968"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Cho, E., Youn, K., Kwon, H., Jeon, J., Cho, W.S., Park, S.J., Son, S.H., Jang, D.S., Shin, C.Y., and Moon, M. (2022). Eugenitol ameliorates memory impairments in 5XFAD mice by reducing A\u03b2 plaques and neuroinflammation. Biomed. Pharmacother., 148.","DOI":"10.1016\/j.biopha.2022.112763"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1097\/WNR.0000000000001783","article-title":"Quercitrin improved cognitive impairment through inhibiting inflammation induced by microglia in Alzheimer\u2019s disease mice","volume":"33","author":"Wang","year":"2022","journal-title":"Neuroreport"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Whitmore, C.A., Haynes, J.R., Behof, W.J., Rosenberg, A.J., Tantawy, M.N., Hachey, B.C., Wadzinski, B.E., Spiller, B.W., Peterson, T.E., and Paffenroth, K.C. (2022). Longitudinal Consumption of Ergothioneine Reduces Oxidative Stress and Amyloid Plaques and Restores Glucose Metabolism in the 5XFAD Mouse Model of Alzheimer\u2019s Disease. Pharmaceuticals, 15.","DOI":"10.3390\/ph15060742"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Lee, D., Kim, N., Jeon, S.H., Gee, M.S., Ju, Y.J., Jung, M.J., Cho, J.S., Lee, Y., Lee, S., and Kil Lee, J. (2022). Hesperidin Improves Memory Function by Enhancing Neurogenesis in a Mouse Model of Alzheimer\u2019s Disease. Nutrients, 14.","DOI":"10.3390\/nu14153125"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Wijesinghe, P., Whitmore, C.A., Campbell, M., Li, C., Tsuyuki, M., To, E., Haynes, J., Pham, W., and Matsubara, J.A. (2023). Ergothioneine, a dietary antioxidant improves amyloid beta clearance in the neuroretina of a mouse model of Alzheimer\u2019s disease. Front. Neurosci., 17.","DOI":"10.3389\/fnins.2023.1107436"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"114473","DOI":"10.1016\/j.expneurol.2023.114473","article-title":"Dual mode of Triphala in the reversal of cognition through gut restoration in antibiotic mediated prolonged dysbiosis condition in 5XFAD mice","volume":"367","author":"Upadhyay","year":"2023","journal-title":"Exp. Neurol."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Lymperopoulos, D., Dedemadi, A.G., Voulgari, M.L., Georgiou, E., Dafnis, I., Mountaki, C., Panagopoulou, E.A., Karvelas, M., Chiou, A., and Karathanos, V.T. (2024). Corinthian Currants Promote the Expression of Paraoxonase-1 and Enhance the Antioxidant Status in Serum and Brain of 5xFAD Mouse Model of Alzheimer\u2019s Disease. Biomolecules, 14.","DOI":"10.3390\/biom14040426"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Nam, Y., Ji, Y.J., Shin, S.J., Park, H.H., Yeon, S.H., Kim, S.Y., Son, R.H., Jang, G.Y., Kim, H.D., and Moon, M. (2024). Platycodon grandiflorum root extract inhibits A\u03b2 deposition by breaking the vicious circle linking oxidative stress and neuroinflammation in Alzheimer\u2019s disease. Biomed. Pharmacother., 177.","DOI":"10.1016\/j.biopha.2024.117090"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Gladen-Kolarsky, N., Monestime, O., Bollen, M., Choi, J., Yang, L., Maga\u00f1a, A.A., Maier, C.S., Soumyanath, A., and Gray, N.E. (2024). Withania somnifera (Ashwagandha) Improves Spatial Memory, Anxiety and Depressive-like Behavior in the 5xFAD Mouse Model of Alzheimer\u2019s Disease. Antioxidants, 13.","DOI":"10.20944\/preprints202408.1265.v1"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Varada, S., Chamberlin, S.R., Bui, L., Brandes, M.S., Gladen-Kolarsky, N., Harris, C.J., Hack, W., Neff, C.J., Brumbach, B.H., and Soumyanath, A. (2025). Oral Asiatic Acid Improves Cognitive Function and Modulates Antioxidant and Mitochondrial Pathways in Female 5xFAD Mice. Nutrients, 17.","DOI":"10.3390\/nu17040729"},{"key":"ref_80","first-page":"F46","article-title":"P-glycoprotein-mediated secretion of a fluorescent cyclosporin analogue by teleost renal proximal tubules","volume":"268","author":"Schramm","year":"1995","journal-title":"Am. J. Physiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1046\/j.1471-4159.2003.01580.x","article-title":"The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice","volume":"84","author":"Farr","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Hartz, A.M.S., Zhong, Y., Shen, A.N., Abner, E.L., and Bauer, B. (2018). Preventing P-gp Ubiquitination Lowers A\u03b2 Brain Levels in an Alzheimer\u2019s Disease Mouse Model. Front. Aging Neurosci., 10.","DOI":"10.3389\/fnagi.2018.00186"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Wolf, A., Bauer, B., Abner, E.L., Ashkenazy-Frolinger, T., and Hartz, A.M. (2016). A Comprehensive Behavioral Test Battery to Assess Learning and Memory in 129S6\/Tg2576 Mice. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0147733"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1523\/JNEUROSCI.0350-15.2016","article-title":"A\u03b240 Reduces P-Glycoprotein at the Blood-Brain Barrier through the Ubiquitin-Proteasome Pathway","volume":"36","author":"Hartz","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1124\/mol.104.001503","article-title":"Rapid regulation of P-glycoprotein at the blood-brain barrier by endothelin-1","volume":"66","author":"Hartz","year":"2004","journal-title":"Mol. Pharmacol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1038\/jcbfm.2008.16","article-title":"Coordinated nuclear receptor regulation of the efflux transporter, Mrp2, and the phase-II metabolizing enzyme, GSTpi, at the blood-brain barrier","volume":"28","author":"Bauer","year":"2008","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1161\/STROKEAHA.111.627562","article-title":"Amyloid-\u03b2 contributes to blood-brain barrier leakage in transgenic human amyloid precursor protein mice and in humans with cerebral amyloid angiopathy","volume":"43","author":"Hartz","year":"2012","journal-title":"Stroke"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1177\/0271678X16655551","article-title":"Matrix metalloproteinases in the brain and blood-brain barrier: Versatile breakers and makers","volume":"36","author":"Rempe","year":"2016","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","article-title":"A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding","volume":"72","author":"Bradford","year":"1976","journal-title":"Anal. Biochem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Series B Stat. Methodol."},{"key":"ref_91","unstructured":"Lenth, R.V., Banfai, B., Bolker, B., Buerkner, P., Gin\u00e9-V\u00e1zquez, I., Herve, M., Jung, M., Love, J., Miguez, F., and Piaskowski, J. (2025, January 22). emmeans: Estimated Marginal Means, aka Least-Squares Means 2022. Available online: https:\/\/cran.r-project.org\/web\/packages\/emmeans\/."},{"key":"ref_92","unstructured":"Montgomery, D.C., Peck, E.A., and Vining, G.G. (2021). Model Adequacy Checking. Introduction to Linear Regression Analysis, Wiley. [6th ed.]."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1037\/0033-2909.87.2.245","article-title":"Tests for comparing elements of a correlation matrix","volume":"87","author":"Steiger","year":"1980","journal-title":"Psychol. Bull."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4352\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:26:38Z","timestamp":1760030798000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4352"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,3]]},"references-count":93,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ijms26094352"],"URL":"https:\/\/doi.org\/10.3390\/ijms26094352","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,3]]}}}