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PPSUS, grant 17\/2551-0001451-0"],"award-info":[{"award-number":["Ed. PPSUS, grant 17\/2551-0001451-0"]}],"id":[{"id":"10.13039\/501100004263","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004263","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Rio Grande do Sul","doi-asserted-by":"publisher","award":["National Institute of Science and Technology in Brain Diseases, Excitotoxicity and Neuroprotection - FAPERGS 17\/2551-0000516-3"],"award-info":[{"award-number":["National Institute of Science and Technology in Brain Diseases, Excitotoxicity and Neuroprotection - FAPERGS 17\/2551-0000516-3"]}],"id":[{"id":"10.13039\/501100004263","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) causes dementia and memory loss in the elderly. Deposits of beta-amyloid peptide and hyperphosphorylated tau protein are present in a brain with AD. A filtrate of Helicobacter pylori\u2019s culture was previously found to induce hyperphosphorylation of tau in vivo, suggesting that bacterial exotoxins could permeate the blood\u2013brain barrier and directly induce tau\u2019s phosphorylation. H. pylori, which infects ~60% of the world population and causes gastritis and gastric cancer, produces a pro-inflammatory urease (HPU). Here, the neurotoxic potential of HPU was investigated in cultured cells and in rats. SH-SY5Y neuroblastoma cells exposed to HPU (50\u2013300 nM) produced reactive oxygen species (ROS) and had an increased [Ca2+]i. HPU-treated BV-2 microglial cells produced ROS, cytokines IL-1\u03b2 and TNF-\u03b1, and showed reduced viability. Rats received daily i.p., HPU (5 \u00b5g) for 7 days. Hyperphosphorylation of tau at Ser199, Thr205 and Ser396 sites, with no alterations in total tau or GSK-3\u03b2 levels, and overexpression of Iba1, a marker of microglial activation, were seen in hippocampal homogenates. HPU was not detected in the brain homogenates. Behavioral tests were performed to assess cognitive impairments. Our findings support previous data suggesting an association between infection by H. pylori and tauopathies such as AD, possibly mediated by its urease.<\/jats:p>","DOI":"10.3390\/ijms23063091","type":"journal-article","created":{"date-parts":[[2022,3,13]],"date-time":"2022-03-13T22:29:43Z","timestamp":1647210583000},"page":"3091","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Helicobacter pylori Urease: Potential Contributions to Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6382-4785","authenticated-orcid":false,"given":"Augusto F.","family":"Uberti","sequence":"first","affiliation":[{"name":"Laboratory of Neurotoxins, Brain Institute of Rio Grande do Sul (BRAINS) and Graduate Program in Medicine and Health Sciences, Pontif\u00edcia Universidade Cat\u00f3lica do Rio Grande do Sul (PUCRS), Porto Alegre CEP 90610-000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Callai-Silva","sequence":"additional","affiliation":[{"name":"Laboratory of Neurotoxins, Brain Institute of Rio Grande do Sul (BRAINS) and Graduate Program in Medicine and Health Sciences, Pontif\u00edcia Universidade Cat\u00f3lica do Rio Grande do Sul (PUCRS), Porto Alegre CEP 90610-000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4935-5211","authenticated-orcid":false,"given":"Matheus V. C.","family":"Grahl","sequence":"additional","affiliation":[{"name":"Laboratory of Neurotoxins, Brain Institute of Rio Grande do Sul (BRAINS) and Graduate Program in Medicine and Health Sciences, Pontif\u00edcia Universidade Cat\u00f3lica do Rio Grande do Sul (PUCRS), Porto Alegre CEP 90610-000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela R.","family":"Piovesan","sequence":"additional","affiliation":[{"name":"Center of Biotechnology, Graduate Program in Cellular and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre CEP 91501-970, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduarda G.","family":"Nachtigall","sequence":"additional","affiliation":[{"name":"Laboratory of Cognition and Memory Neurobiology, Brain Institute of Rio Grande do Sul (BRAINS) and Graduate Program in Biomedical Gerontology, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre CEP 90610-000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiane R. G.","family":"Furini","sequence":"additional","affiliation":[{"name":"Laboratory of Cognition and Memory Neurobiology, Brain Institute of Rio Grande do Sul (BRAINS) and Graduate Program in Biomedical Gerontology, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre CEP 90610-000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7027-2445","authenticated-orcid":false,"given":"Celia Regina","family":"Carlini","sequence":"additional","affiliation":[{"name":"Laboratory of Neurotoxins, Brain Institute of Rio Grande do Sul (BRAINS) and Graduate Program in Medicine and Health Sciences, Pontif\u00edcia Universidade Cat\u00f3lica do Rio Grande do Sul (PUCRS), Porto Alegre CEP 90610-000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e12454","DOI":"10.1111\/hel.12454","article-title":"Review: Impact of Helicobacter pylori on Alzheimer\u2019s disease: What do we know so far?","volume":"23","author":"Doulberis","year":"2018","journal-title":"Helicobacter"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1053\/j.gastro.2017.04.022","article-title":"Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis","volume":"153","author":"Hooi","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.giec.2011.07.011","article-title":"The prevalence and incidence of Helicobacter pylori-associated peptic ulcer disease and upper gastrointestinal bleeding throughout the world","volume":"21","author":"Wang","year":"2011","journal-title":"Gastrointest. Endosc. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1146\/annurev.micro.54.1.615","article-title":"The disease spectrum of Helicobacter pylori: The immunopathogenesis of gastroduodenal ulcer and gastric cancer","volume":"54","author":"Ernst","year":"2000","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e12636","DOI":"10.1111\/hel.12636","article-title":"Review: Helicobacter pylori and extragastric diseases","volume":"24","author":"Franceschi","year":"2019","journal-title":"Helicobacter"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Baj, J., Forma, A., Flieger, W., Morawska, I., Michalski, A., Buszewicz, G., Sitarz, E., Portincasa, P., Garruti, G., and Flieger, M. (2021). Helicobacter pylori Infection and Extragastric Diseases\u2014A Focus on the Central Nervous System. Cells, 10.","DOI":"10.3390\/cells10092191"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1136\/heart.88.1.43","article-title":"Prospective analysis of the association of infection with CagA bearing strains of Helicobacter pylori and coronary heart disease","volume":"88","author":"Singh","year":"2002","journal-title":"Heart"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/j.dld.2012.05.001","article-title":"Glaucoma and Helicobacter pylori: Eyes \u201cwide open\u201d!","volume":"44","author":"Kountouras","year":"2012","journal-title":"Dig. Liver Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0022-510X(01)00507-X","article-title":"Helicobacter pylori infection as an independent risk factor for cerebral ischemia of atherothrombotic origin","volume":"186","author":"Grau","year":"2001","journal-title":"J. Neurol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"835","DOI":"10.4251\/wjgo.v13.i8.835","article-title":"Helicobacter pylori infection and other bacteria in pancreatic cancer and autoimmune pancreatitis","volume":"13","author":"Kunovsky","year":"2021","journal-title":"World J. Gastrointest. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1080\/00207450902782083","article-title":"Increased Cerebrospinal Fluid Helicobacter Pylori Antibody in Alzheimer\u2019s Disease","volume":"119","author":"Kountouras","year":"2009","journal-title":"Int. J. Neurosci."},{"key":"ref_12","first-page":"938","article-title":"Relationship between Helicobacter pylori infection and Alzheimer disease","volume":"66","author":"Kountouras","year":"2006","journal-title":"J. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1111\/j.1468-1331.2007.01827.x","article-title":"Association between Helicobacter pylori infection and mild cognitive impairment","volume":"14","author":"Kountouras","year":"2007","journal-title":"Eur. J. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Lolekha, P., Sriphanom, T., and Vilaichone, R.-K. (2021). Helicobacter pylori eradication improves motor fluctuations in advanced Parkinson\u2019s disease patients: A prospective cohort study (HP-PD trial). PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0251042"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1007\/s00415-021-10473-1","article-title":"Helicobacter pylori infection is associated with a poor response to levodopa in patients with Parkinson\u2019s disease: A systematic review and meta-analysis","volume":"269","author":"Zhong","year":"2021","journal-title":"J. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1111\/jgs.12065","article-title":"Does Helicobacter pylori infection increase incidence of dementia? The Personnes Ag\u00e9es QUID Study","volume":"61","author":"Letenneur","year":"2013","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.ejim.2004.05.008","article-title":"Helicobacter pylori and Alzheimer\u2019s disease: A possible link","volume":"15","author":"Malaguarnera","year":"2004","journal-title":"Eur. J. Intern. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"153","DOI":"10.3233\/JAD-140198","article-title":"Helicobacter pylori Filtrate Induces Alzheimer-Like Tau Hyperphosphorylation by Activating Glycogen Synthase Kinase-3 beta","volume":"43","author":"Wang","year":"2014","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1046\/j.1523-5378.2001.00014.x","article-title":"Cell lysis is responsible for the appearance of extracellular urease in Helicobacter pylori","volume":"6","author":"Marcus","year":"2001","journal-title":"Helicobacter"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/0016-5085(90)90957-3","article-title":"Urea protects Helicobacter (Campylobacter) pylori from the bactericidal effect of acid","volume":"99","author":"Marshall","year":"1990","journal-title":"Gastroenterology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/35073084","article-title":"Living dangerously: How Helicobacter pylori survives in the human stomach","volume":"2","author":"Montecucco","year":"2001","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2470","DOI":"10.1128\/iai.59.7.2470-2475.1991","article-title":"Essential role of urease in pathogenesis of gastritis induced by Helicobacter pylori in gnotobiotic piglets","volume":"59","author":"Eaton","year":"1991","journal-title":"Infect. Immun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3586","DOI":"10.1128\/iai.62.8.3586-3589.1994","article-title":"A urease-negative mutant of Helicobacter pylori constructed by allelic exchange mutagenesis lacks the ability to colonize the nude mouse stomach","volume":"62","author":"Tsuda","year":"1994","journal-title":"Infect. Immun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4723","DOI":"10.1007\/s00253-016-7495-7","article-title":"Biomarkers and diagnostic tools for detection of Helicobacter pylori","volume":"100","author":"Khalilpour","year":"2016","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_25","first-page":"232","article-title":"Determination of optimal time for reading of rapid urease test diagnosis of Helicobacter pylori","volume":"13","author":"Eslaminejad","year":"2020","journal-title":"Gastroenterol. Hepatol. Bed Bench"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.toxicon.2015.11.020","article-title":"Ureases as multifunctional toxic proteins: A review","volume":"110","author":"Carlini","year":"2015","journal-title":"Toxicon"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.jare.2018.05.010","article-title":"Ureases: Historical aspects, catalytic, and non-catalytic properties\u2014A review","volume":"13","author":"Kappaun","year":"2018","journal-title":"J. Adv. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.1111\/j.1582-4934.2009.00901.x","article-title":"Helicobacter pylori urease activates blood platelets through a lipoxygenase-mediated pathway","volume":"14","author":"Wassermann","year":"2010","journal-title":"J. Cell. Mol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2447","DOI":"10.3389\/fmicb.2017.02447","article-title":"The impact of Helicobacter pylori urease upon platelets and consequent contributions to inflammation","volume":"8","author":"Staniscuaski","year":"2017","journal-title":"Front. Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.toxicon.2013.02.009","article-title":"Pro-inflammatory properties and neutrophil activation by Helicobacter pylori urease","volume":"69","author":"Uberti","year":"2013","journal-title":"Toxicon"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1111\/jth.13911","article-title":"Inflammation and thrombosis: Roles of neutrophils, platelets and endothelial cells and their interactions in thrombus formation during sepsis","volume":"16","author":"Iba","year":"2017","journal-title":"J. Thromb. Haemost."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.3389\/fmicb.2017.01883","article-title":"A new role for Helicobacter pylori urease: Contributions to angiogenesis","volume":"8","author":"Uberti","year":"2017","journal-title":"Front. Microbiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1053\/j.gastro.2008.10.011","article-title":"Helicobacter pylori dysregulation of gastric epithelial tight junctions by urease-mediated myosin II activation","volume":"136","author":"Wroblewski","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e12573","DOI":"10.1111\/hel.12573","article-title":"Helicobacter pylori urease induces pro-inflammatory effects and differentiation of human endothelial cells: Cellular and molecular mechanism","volume":"24","author":"Uberti","year":"2019","journal-title":"Helicobacter"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"667","DOI":"10.3233\/JAD-132282","article-title":"Analysis of matrix metallo-proteases and the plasminogen system in mild cognitive impairment and Alzheimer\u2019s disease cerebrospinal fluid","volume":"40","author":"Hanzel","year":"2014","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1016\/j.bbi.2011.02.008","article-title":"Brain inflammation is induced by co-morbidities and risk factors for stroke","volume":"25","author":"Drake","year":"2011","journal-title":"Brain Behav. Immun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.neuroscience.2015.03.007","article-title":"Neuroinflammation in the normal aging hippocampus","volume":"309","author":"Barrientos","year":"2015","journal-title":"Neuroscience"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1111\/j.1365-2958.2010.07307.x","article-title":"Biochemical and functional characterization of Helicobacter pylori vesicles","volume":"77","author":"Olofsson","year":"2010","journal-title":"Mol. Microbiol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Bruno, L., Karagil, S., Mahmood, A., Elbediwy, A., Stolinski, M., and Mackenzie, F.E. (2021). Mechanosensing and the Hippo Pathway in Microglia: A Potential Link to Alzheimer\u2019s Disease Pathogenesis?. Cells, 10.","DOI":"10.3390\/cells10113144"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.exger.2015.04.010","article-title":"Effects of antibodies to phosphorylated and non-phosphorylated tau on in vitro tau phosphorylation at Serine-199: Preliminary report","volume":"67","author":"Loeffler","year":"2015","journal-title":"Exp. Gerontol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1111\/nan.12084","article-title":"Phosphorylation of tau protein at sites Ser(396-404) is one of the earliest events in Alzheimer\u2019s disease and Down syndrome","volume":"40","author":"Mondragonrodriguez","year":"2014","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_42","first-page":"578373","article-title":"Tau Phosphorylation by GSK3 in Different Conditions","volume":"2012","author":"Avila","year":"2012","journal-title":"Int. J. Alzheimer\u2019s Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1001\/archneur.65.10.1368","article-title":"Association of GSK3B with Alzheimer disease and frontotemporal dementia","volume":"65","author":"Schaffer","year":"2008","journal-title":"Arch. Neurol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"S141","DOI":"10.3233\/JAD-2012-129025","article-title":"GSK3 and tau: Two convergence points in Alzheimer\u2019s disease","volume":"33","author":"Hernandez","year":"2013","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.molmed.2009.01.003","article-title":"Tau phosphorylation: The therapeutic challenge for neurodegenerative disease","volume":"15","author":"Hanger","year":"2009","journal-title":"Trends Mol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1111\/j.2044-8295.1950.tb00262.x","article-title":"Novelty and curiosity as determinants of exploratory behaviour","volume":"41","author":"Berlyne","year":"1950","journal-title":"Br. J. Psychol. Gen. Sect."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/S0149-7634(96)00058-9","article-title":"Anxiety, defence and the elevated plus-maze","volume":"21","author":"Rodgers","year":"1997","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s00011-009-8075-4","article-title":"In vitro effects of Helicobacter pylori-induced infection in gastric epithelial AGS cells on microglia-mediated toxicity in neuroblastoma SH-SY5Y cells","volume":"58","author":"Lo","year":"2009","journal-title":"Inflamm. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1089\/ars.2007.2007","article-title":"Reactive oxygen species and endothelial activation","volume":"10","author":"Anilkumar","year":"2008","journal-title":"Antioxidants Redox Signal."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1089\/ars.2008.2220","article-title":"NADPH oxidase-dependent signaling in endothelial cells: Role in physiology and pathophysiology","volume":"11","author":"Frey","year":"2009","journal-title":"Antioxidants Redox Signal."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Islam, M. (2020). Calcium Signaling and Gene Expression. Calcium Signaling. Advances in Experimental Medicine and Biology, Springer.","DOI":"10.1007\/978-3-030-12457-1"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s001090000077","article-title":"Molecular mechanisms of calcium-dependent excitotoxicity","volume":"78","author":"Sattler","year":"2000","journal-title":"J. Mol. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1098\/rstb.1994.0102","article-title":"Block of neuronal apoptosis by a sustained increase of steady-state free Ca2+ concentration","volume":"345","author":"Franklin","year":"1994","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/0166-2236(92)90103-F","article-title":"Suppression of programmed neuronal death by sustained elevation of cytoplasmic calcium","volume":"15","author":"Franklin","year":"1992","journal-title":"Trends Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/ncb3114","article-title":"Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB","volume":"17","author":"Medina","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/nrm1150","article-title":"Regulation of cell death: The calcium-apoptosis link","volume":"4","author":"Orrenius","year":"2003","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.ntt.2016.11.004","article-title":"Anesthetic neurotoxicity: Apoptosis and autophagic cell death mediated by calcium dysregulation","volume":"60","author":"Yang","year":"2017","journal-title":"Neurotoxicology Teratol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1002\/jnr.490310405","article-title":"An immortalized cell line expresses properties of activated microglial cells","volume":"31","author":"Bocchini","year":"1992","journal-title":"J. Neurosci. Res."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Grahl, M.V.C., Uberti, A.F., Broll, V., Bacaicoa-Caruso, P., Meirelles, E.F., and Carlini, C.R. (2021). Proteus mirabilis Urease: Unsuspected Non-Enzymatic Properties Relevant to Pathogenicity. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22137205"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"576383","DOI":"10.1155\/2013\/576383","article-title":"The Innate Immune System in Alzheimer\u2019s Disease","volume":"2013","author":"Boutajangout","year":"2013","journal-title":"Int. J. Cell Biol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Hunter, J.M., Kwan, J., Malek-Ahmadi, M., Maarouf, C.L., Kokjohn, T.A., Belden, C., Sabbagh, M.N., Beach, T.G., and Roher, A.E. (2012). Morphological and pathological evolution of the brain microcirculation in aging and Alzheimer\u2019s disease. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0036893"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1006\/exnr.2000.7393","article-title":"Interleukin-1 promotes expression and phosphorylation of neurofilament and tau proteins in vivo","volume":"163","author":"Sheng","year":"2000","journal-title":"Exp. Neurol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3297","DOI":"10.1172\/JCI79337","article-title":"Helicobacter urease-induced activation of the TLR2\/NLRP3\/IL-18 axis protects against asthma","volume":"125","author":"Koch","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1476-9255-8-7","article-title":"Endotoxin-activated microglia injure brain derived endothelial cells via NF-\u03baB, JAK-STAT and JNK stress kinase pathways","volume":"8","author":"Kacimi","year":"2011","journal-title":"J. Inflamm."},{"key":"ref_65","first-page":"175","article-title":"Helicobacter pylori urease induces mouse death","volume":"35","author":"Baik","year":"2005","journal-title":"J. Bacteriol. Virol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/j.1600-0773.1984.tb01912.x","article-title":"Central nervous effects of the convulsant protein canatoxin","volume":"54","author":"Carlini","year":"1984","journal-title":"Acta Pharmacol. Toxicol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"152737","DOI":"10.1016\/j.tox.2021.152737","article-title":"Neurotoxic and convulsant effects induced by jack bean ureases on the mammalian nervous system","volume":"454","author":"Almeida","year":"2021","journal-title":"Toxicology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"57","DOI":"10.3389\/fnmol.2016.00057","article-title":"Ammonia as a Potential Neurotoxic Factor in Alzheimer\u2019s Disease","volume":"9","author":"Adlimoghaddam","year":"2016","journal-title":"Front. Mol. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1007\/s12640-011-9269-4","article-title":"Alterations of blood brain barrier function in hyperammonemia: An overview","volume":"21","author":"Skowronska","year":"2012","journal-title":"Neurotox. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/j.1471-4159.2012.07669.x","article-title":"Ammonia increases paracellular permeability of rat brain endothelial cells by a mechanism encompassing oxidative\/nitrosative stress and activation of matrix metalloproteinases","volume":"121","author":"Ruszkiewicz","year":"2012","journal-title":"J. Neurochem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"e1143544","DOI":"10.1080\/21688370.2016.1143544","article-title":"Heterogeneity of the blood-brain barrier","volume":"4","author":"Wilhelm","year":"2016","journal-title":"Tissue Barriers"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2877","DOI":"10.3389\/fimmu.2018.02877","article-title":"Circumventricular Organs and Parasite Neurotropism: Neglected Gates to the Brain?","volume":"9","author":"Bentivoglio","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"586","DOI":"10.4103\/1673-5374.266908","article-title":"Extracellular vesicles in the diagnosis and treatment of central nervous system diseases","volume":"15","author":"Shaimardanova","year":"2020","journal-title":"Neural Regen. Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"fnv076","DOI":"10.1093\/femsle\/fnv076","article-title":"Helicobacter pylori vesicles carrying CagA localize in the vicinity of cell-cell contacts and induce histone H1 binding to ATP in epithelial cells","volume":"362","author":"Turkina","year":"2015","journal-title":"FEMS Microbiol. Lett."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"454","DOI":"10.4161\/gmic.27001","article-title":"Signal transduction of Helicobacter pylori during interaction with host cell protein receptors of epithelial and immune cells","volume":"4","author":"Pachathundikandi","year":"2013","journal-title":"Gut Microbes"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1021\/acs.molpharmaceut.8b00985","article-title":"Cluster of Differentiation 46 Is the Major Receptor in Human Blood-Brain Barrier Endothelial Cells for Uptake of Exosomes Derived from Brain-Metastatic Melanoma Cells (SK-Mel-28)","volume":"16","author":"Kuroda","year":"2019","journal-title":"Mol. Pharm."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1039\/C4MB00747F","article-title":"Metabolomic investigation of systemic manifestations associated with Alzheimer\u2019s disease in the APP\/PS1 transgenic mouse model","volume":"11","author":"Vitorica","year":"2015","journal-title":"Mol. BioSyst."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1006\/abbi.1997.9898","article-title":"Stimulation of calcium influx and platelet activation by canatoxin: Methoxyverapamil inhibition and downregulation by cGMP","volume":"339","author":"Ghazaleh","year":"1997","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/bs.apcsb.2017.02.001","article-title":"Neuroinflammation in Alzheimer\u2019s Disease: The Preventive and Therapeutic Potential of Polyphenolic Nutraceuticals","volume":"108","author":"Sawikr","year":"2017","journal-title":"Adv. Protein Chem. Struct. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1093\/gerona\/gly127","article-title":"Obesity in Aging Exacerbates Neuroinflammation, Dysregulating Synaptic Function-Related Genes and Altering Eicosanoid Synthesis in the Mouse Hippocampus: Potential Role in Impaired Synaptic Plasticity and Cognitive Decline","volume":"74","author":"Tucsek","year":"2019","journal-title":"J. Gerontol. Ser. A Biol. Sci. Med. Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"105212","DOI":"10.1016\/j.neuint.2021.105212","article-title":"Cellular and molecular influencers of neuroinflammation in Alzheimer\u2019s disease: Recent concepts & roles","volume":"151","author":"Ghosh","year":"2021","journal-title":"Neurochem. Int."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Biringer, R.G. (2019). The Role of Eicosanoids in Alzheimer\u2019s Disease. Int. J. Environ. Res. Public Health, 16.","DOI":"10.3390\/ijerph16142560"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s13195-017-0283-5","article-title":"On the path to 2025: Understanding the Alzheimer\u2019s disease continuum","volume":"9","author":"Aisen","year":"2017","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2478","DOI":"10.1523\/JNEUROSCI.22-07-02478.2002","article-title":"The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS","volume":"22","author":"Lehnardt","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.jnutbio.2012.06.011","article-title":"Epigallocatechin-3-gallate prevents systemic inflammation-induced memory deficiency and amyloidogenesis via its anti-neuroinflammatory properties","volume":"24","author":"Lee","year":"2013","journal-title":"J. Nutr. Biochem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"553","DOI":"10.33549\/physiolres.933480","article-title":"Lipopolysaccharide-induced memory impairment in rats: A model of Alzheimer\u2019s disease","volume":"66","author":"Zakaria","year":"2017","journal-title":"Physiol. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.neuroscience.2015.04.048","article-title":"Tracing the trajectory of behavioral impairments and oxidative stress in an animal model of neonatal inflammation","volume":"298","author":"MacRae","year":"2015","journal-title":"Neuroscience"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.bbi.2020.07.034","article-title":"Exposure to bacterial lipopolysaccharidein early life affects the expression of ionotropic glutamate receptor genes and is accompanied by disturbances in long-term potentiation and cognitive functions in young rats","volume":"90","author":"Zubareva","year":"2020","journal-title":"Brain Behav. Immun."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"66","DOI":"10.3389\/fnagi.2014.00066","article-title":"Helicobacter pylori filtrate impairs spatial learning and memory in rats and increases beta-amyloid by enhancing expression of presenilin-2","volume":"6","author":"Wang","year":"2014","journal-title":"Front. Aging Neurosci."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/0166-4328(88)90157-X","article-title":"A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data","volume":"31","author":"Ennaceur","year":"1988","journal-title":"Behav. Brain Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1002\/hipo.20656","article-title":"Beta-adrenergic receptors link NO\/sGC\/PKG signaling to BDNF expression during the consolidation of object recognition long-term memory","volume":"20","author":"Furini","year":"2010","journal-title":"Hippocampus"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/6\/3091\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:35:49Z","timestamp":1760135749000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/6\/3091"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,13]]},"references-count":91,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["ijms23063091"],"URL":"https:\/\/doi.org\/10.3390\/ijms23063091","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202201.0194.v1","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,13]]}}}