{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T05:06:51Z","timestamp":1781586411200,"version":"3.54.5"},"reference-count":132,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T00:00:00Z","timestamp":1672876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a leading neurodegenerative disease with deteriorating cognition as its main clinical sign. In addition to the clinical history, it is characterized by the presence of two neuropathological hallmark lesions; amyloid-beta (A\u03b2) and neurofibrillary tangles (NFTs), identified in the brain at post-mortem in specific anatomical areas. Recently, it was discovered that NFTs occur initially in the subcortical nuclei, such as the locus coeruleus in the pons, and are said to spread from there to the cerebral cortices and the hippocampus. This contrasts with the prior acceptance of their neuropathology in the enthorinal cortex and the hippocampus. The Braak staging system places the accumulation of phosphorylated tau (p-tau) binding to NFTs in the locus coeruleus and other subcortical nuclei to precede stages I\u2013IV. The locus coeruleus plays diverse psychological and physiological roles within the human body including rapid eye movement sleep disorder, schizophrenia, anxiety, and depression, regulation of sleep-wake cycles, attention, memory, mood, and behavior, which correlates with AD clinical behavior. In addition, the locus coeruleus regulates cardiovascular, respiratory, and gastrointestinal activities, which have only recently been associated with AD by modern day research enabling the wider understanding of AD development via comorbidities and microbial dysbiosis. The focus of this narrative review is to explore the modes of neurodegeneration taking place in the locus coeruleus during the natural aging process of the trigeminal nerve connections from the teeth and microbial dysbiosis, and to postulate a pathogenetic mechanism due to periodontal damage and\/or infection focused on Treponema denticola.<\/jats:p>","DOI":"10.3390\/ijerph20021007","type":"journal-article","created":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T01:48:19Z","timestamp":1672969699000},"page":"1007","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Locus Coeruleus Dysfunction and Trigeminal Mesencephalic Nucleus Degeneration: A Cue for Periodontal Infection Mediated Damage in Alzheimer\u2019s Disease?"],"prefix":"10.3390","volume":"20","author":[{"given":"Flavio","family":"Pisani","sequence":"first","affiliation":[{"name":"Programme Lead, MSc\/MClinDent in Clinical Periodontology, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston PR1 2HE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerio","family":"Pisani","sequence":"additional","affiliation":[{"name":"I.R.C.C.S. \u201cSanta Lucia\u201d Foundation, Neurology and Neurorehabilitation Unit, Via Ardeatina, 306, 00179 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Arcangeli","sequence":"additional","affiliation":[{"name":"Azienda Sanitaria Locale ASLRM1, Nuovo Regina Margherita Hospital, Geriatric Department-Advanced Centre for Dementia and Cognitive Disorders, Via Emilio Morosini, 30, 00153 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Harding","sequence":"additional","affiliation":[{"name":"Dementia and Neurodegenerative Disease Research Group, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston PR1 2HE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sim K.","family":"Singhrao","sequence":"additional","affiliation":[{"name":"Dementia and Neurodegenerative Disease Research Group, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston PR1 2HE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jalz.2011.10.007","article-title":"National Institute on Aging-Alzheimer\u2019s Association guidelines for the neuropathologic assessment of Alzheimer\u2019s disease","volume":"8","author":"Hyman","year":"2012","journal-title":"Alzheimers Dement."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological stageing of Alzheimer-related changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1097\/NEN.0b013e318232a379","article-title":"Stages of the pathologic process in Alzheimer disease: Age categories from 1 to 100 years","volume":"70","author":"Braak","year":"2011","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"80","DOI":"10.3389\/fnana.2017.00080","article-title":"The neuroanatomy of the reticular nucleus locus coeruleus in Alzheimer\u2019s disease","volume":"11","author":"Giorgi","year":"2017","journal-title":"Front. Neuroanat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.tics.2016.01.001","article-title":"The locus coeruleus: Essential for maintaining cognitive function and the aging brain","volume":"20","author":"Mather","year":"2016","journal-title":"Trends Cogn. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.ynstr.2015.09.002","article-title":"Locus coeruleus, norepinephrine and A\u03b2 peptides in Alzheimer\u2019s disease","volume":"2","author":"Ross","year":"2015","journal-title":"Neurobiol. Stress"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e148","DOI":"10.1038\/emm.2014.121","article-title":"Sleep, circadian rhythms, and the pathogenesis of Alzheimer disease","volume":"47","author":"Musiek","year":"2015","journal-title":"Exp. Mol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1146\/annurev.neuro.28.061604.135709","article-title":"An integrative theory of locus coeruleus-norepinephrine function: Adaptive gain and optimal performance","volume":"28","author":"Cohen","year":"2005","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1101\/lm.037283.114","article-title":"Projection specificity in heterogeneous locus coeruleus cell populations: Implications for learning and memory","volume":"22","author":"Uematsu","year":"2015","journal-title":"Learn. Mem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/S0165-0173(03)00143-7","article-title":"The locus coeruleus\u2013noradrenergic system: Modulation of behavioral state and state-dependent cognitive processes","volume":"42","author":"Berridge","year":"2003","journal-title":"Brain Res. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"R1051","DOI":"10.1016\/j.cub.2015.09.039","article-title":"Organization of the locus coeruleus-norepinephrine system","volume":"25","author":"Schwarz","year":"2015","journal-title":"Curr. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1093\/aje\/154.7.635","article-title":"Diabetes Mellitus and Risk of Alzheimer\u2019s Disease and Dementia with Stroke in a Multiethnic Cohort","volume":"154","author":"Luchsinger","year":"2001","journal-title":"Am. J. Epidemiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1179\/016164106X130362","article-title":"How do heart disease and stroke become risk factors for Alzheimer\u2019s disease?","volume":"28","year":"2006","journal-title":"Neurol. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.14219\/jada.archive.2007.0046","article-title":"Tooth loss, dementia and neuropathology in the Nun Study","volume":"138","author":"Stein","year":"2007","journal-title":"J. Am. Dent. Assoc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s13195-017-0282-6","article-title":"Association between chronic periodontitis and the risk of Alzheimer\u2019s disease: A retrospective, population-based, matched-cohort study","volume":"9","author":"Chen","year":"2017","journal-title":"Alzheimers Res. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.3233\/JAD-191068","article-title":"Diabetes mellitus increases risk of incident dementia in APOE\u03b54 carriers: A meta-analysis","volume":"74","author":"Li","year":"2020","journal-title":"J. Alzheimers Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.euroneuro.2020.12.013","article-title":"A case-control study of the locus coeruleus degeneration in Alzheimer\u2019s disease","volume":"43","author":"Hou","year":"2021","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/0022-510X(81)90031-9","article-title":"Cell loss in the locus coeruleus in senile dementia of Alzheimer type","volume":"49","author":"Tomlinson","year":"1981","journal-title":"J. Neurol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1212\/WNL.32.2.164","article-title":"Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia","volume":"32","author":"Bondareff","year":"1982","journal-title":"Neurology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1002\/ana.410320510","article-title":"Disease-specific patterns of locus coeruleus cell loss","volume":"32","author":"German","year":"1992","journal-title":"Ann. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1192\/bjp.135.3.216","article-title":"Changes in the brain catecholamines in patients with dementia of Alzheimer type","volume":"135","author":"Adolfsson","year":"1979","journal-title":"Br. J. Psychiatry"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3393","DOI":"10.1111\/j.1460-9568.2006.05223.x","article-title":"Degeneration of noradrenergic fibres from the locus coeruleus causes tight-junction disorganisation in the rat brain","volume":"24","author":"Kalinin","year":"2006","journal-title":"Eur. J. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.brainresrev.2004.02.002","article-title":"Noradrenergic mechanisms in neurodegenerative diseases: A theory","volume":"45","author":"Marien","year":"2004","journal-title":"Brain Res. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"15291","DOI":"10.1074\/jbc.M113.458901","article-title":"Norepinephrine modulates the motility of resting and activated microglia via different adrenergic receptors","volume":"288","author":"Gyoneva","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/S0197-4580(00)00124-X","article-title":"Inflammation and Alzheimer\u2019s disease","volume":"21","author":"Akiyama","year":"2000","journal-title":"Neurobiol. Aging"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1080\/13550280290100969","article-title":"Local neuroinflammation and the progression of Alzheimer\u2019s disease","volume":"8","author":"McGeer","year":"2002","journal-title":"J. Neurovirol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","article-title":"Neuroinflammation in Alzheimer\u2019s disease","volume":"14","author":"Heneka","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1001\/archpsyc.1987.01800170026005","article-title":"Age and histopathologic heterogeneity in Alzheimer\u2019s disease: Evidence for subtypes","volume":"44","author":"Bondareff","year":"1987","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1523\/JNEUROSCI.4236-05.2006","article-title":"Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice","volume":"26","author":"Heneka","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/0304-3940(86)90336-8","article-title":"Loss of nerve cells from locus coeruleus iin Alzheimer\u2019s disease is topographically arranged","volume":"64","author":"Marcyniuk","year":"1986","journal-title":"Neurosci. Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.brainresbull.2018.08.002","article-title":"DSP-4 induced depletion of brain noradrenaline and increased 6-hertz psychomotor seizure susceptibility in mice is prevented by sodium valproate","volume":"142","author":"Jahan","year":"2018","journal-title":"Brain Res. Bull."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1016\/j.neurobiolaging.2006.06.003","article-title":"Noradrenaline deficiency in brain increases \u03b2-amyloid plaque burden in an animal model of Alzheimer\u2019s disease","volume":"28","author":"Kalinin","year":"2007","journal-title":"Neurobiol. Aging"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.biopsych.2012.06.013","article-title":"Selective loss of noradrenaline exacerbates early cognitive dysfunction and synaptic deficits in APP\/PS1 mice","volume":"73","author":"Hammerschmidt","year":"2013","journal-title":"Biol. Psychiatry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/cne.901260301","article-title":"The isodendritic core of the brain stem","volume":"126","author":"Nauta","year":"1966","journal-title":"J. Comp. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3233\/JAD-142682","article-title":"Turning on the Light Within: Subcortical Nuclei of the Isodentritic Core and their Role in Alzheimer\u2019s Disease Pathogenesis","volume":"46","author":"Theofilas","year":"2015","journal-title":"J Alzheimers Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.jalz.2016.06.2362","article-title":"Locus coeruleus volume and cell population changes during Alzheimer\u2019s disease progression: A stereological study in human postmortem brains with potential implication for early-stage biomarker discovery","volume":"13","author":"Theofilas","year":"2017","journal-title":"Alzheimers Dement."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/0006-8993(76)90207-9","article-title":"The locus coeruleus: A cytoarchitectonic, Golgi and immunohistochemical study in the albino rat","volume":"110","author":"Swanson","year":"1976","journal-title":"Brain Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1073\/pnas.72.2.659","article-title":"Ultrastructural localization of tyrosine hydroxylase in noradrenergic neurons of brain","volume":"72","author":"Pickel","year":"1975","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1007\/s00401-020-02248-1","article-title":"The mechanistic link between selective vulnerability of the locus coeruleus and neurodegeneration in Alzheimer\u2019s disease","volume":"141","author":"Matchett","year":"2021","journal-title":"Acta Neuropathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/0306-4522(90)90410-6","article-title":"Neurotransmitters and neuropeptides within the mesencephalic trigeminal nucleus of the rat: An immunohistochemical analysis","volume":"37","author":"Copray","year":"1990","journal-title":"Neuroscience"},{"key":"ref_41","first-page":"167","article-title":"Trigeminal representations of the masticatory and extraocular proprioceptors as revealed by horseradish peroxidase retrograde transport","volume":"23","author":"Batini","year":"1975","journal-title":"Exp. Brain Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1037\/0735-7044.97.1.62","article-title":"Trigeminal orosensation and ingestive behavior in the rat","volume":"97","author":"Jacquin","year":"1983","journal-title":"Behav. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1113\/jphysiol.1978.sp012353","article-title":"The projection of jaw elevator muscle spindle afferents to fifth nerve motoneurones in the cat","volume":"279","author":"Appenteng","year":"1978","journal-title":"J. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1002\/cne.902680403","article-title":"The central projection of masticatory afferent fibers to the trigeminal sensory nuclear complex and upper cervical spinal cord","volume":"268","author":"Shigenaga","year":"1988","journal-title":"J. Comp. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/0006-8993(88)91206-1","article-title":"Morphology of single mesencephalic trigeminal neurons innervating masseter muscle of the cat","volume":"445","author":"Shigenaga","year":"1988","journal-title":"Brain Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/0361-9230(79)90051-0","article-title":"The effects of stimulation of trigeminal sensory afferents upon caudate units in cats","volume":"4","author":"Lidsky","year":"1979","journal-title":"Brain Res. Bull."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1002\/cne.902280212","article-title":"The distribution of afferent neurones in the mesencephalic nucleus of the fifth nerve in the cat","volume":"228","author":"Gottlieb","year":"1984","journal-title":"J. Comp. Neurol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/S0003-9969(97)00081-2","article-title":"Quantitative and somatotopic mapping of neurons in the trigeminal mesencephalic nucleus and ganglion innervating teeth in monkey and baboon","volume":"42","author":"Hassanali","year":"1997","journal-title":"Arch. Oral Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1679\/aohc.63.369","article-title":"Time-related changes in periodontal mechanoreceptors in rat molars after the loss of occlusal stimuli","volume":"63","author":"Muramoto","year":"2000","journal-title":"Arch. Histol. Cytol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.3233\/JAD-200257","article-title":"Neurodegeneration of trigeminal mesencephalic neurons by the tooth loss triggers the progression of Alzheimer\u2019s disease in 3\u00d7 Tg-AD model mice","volume":"76","author":"Goto","year":"2020","journal-title":"J. Alzheimers Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1007\/BF00230940","article-title":"The reaction of mesencephalic trigeminal neurons to peripheral nerve transection in the adult rat","volume":"90","author":"Raappana","year":"1992","journal-title":"Exp. Brain Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1113\/jphysiol.1989.sp017519","article-title":"Distribution of mesencephalic nucleus and trigeminal ganglion mechanoreceptors in the periodontal ligament of the cat","volume":"410","author":"Linden","year":"1989","journal-title":"J. Physiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"323","DOI":"10.2535\/ofaj1936.63.5_323","article-title":"Fine structure of probable sensory nerve endings in human periodontal ligaments","volume":"63","author":"Nakamura","year":"1986","journal-title":"Okajimas Folia Anat. Jpn."},{"key":"ref_54","unstructured":"de Reuck, A.V.S., and Knight, J. (1966). Fine Structure of the Receptor Organs and its Probable Functional Significance. Ciba Foundation Symposium\u2014Hormonal Factors in Carbohydrate Metabolism (Colloquia on Endocrinology)."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1113\/jphysiol.1982.sp014350","article-title":"The distribution of mechanoreceptors in the periodontal ligament of the mandibular canine tooth of the cat","volume":"330","author":"Cash","year":"1982","journal-title":"J. Physiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1152\/physrev.1970.50.3.297","article-title":"Mechanoreceptor function","volume":"50","author":"Catton","year":"1970","journal-title":"Physiol. Rev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s00784-017-2264-2","article-title":"Oral hygiene and oral health in older people with dementia: A comprehensive review with focus on oral soft tissues","volume":"22","author":"Delwel","year":"2018","journal-title":"Clin. Oral Investig."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"553","DOI":"10.3233\/JPD-181367","article-title":"No Significant Difference in Cognitive Decline and Mortality between Parkinson\u2019s Disease Dementia and Dementia with Lewy Bodies: Naturalistic Longitudinal Data from the Swedish Dementia Registry","volume":"8","author":"Fereshtehnejad","year":"2018","journal-title":"J. Parkinsons Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"437","DOI":"10.3233\/JAD-2008-13408","article-title":"Alzheimer\u2019s disease and peripheral infections: The possible contribution from periodontal infections, model and hypothesis","volume":"13","author":"Kamer","year":"2008","journal-title":"J. Alzheimers Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/B978-0-12-396492-2.00004-7","article-title":"Chapter Four\u2014Recent Developments in Targeting Neuroinflammation in Disease","volume":"Volume 47","author":"Desai","year":"2012","journal-title":"Annual Reports in Medicinal Chemistry"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"eaau3333","DOI":"10.1126\/sciadv.aau3333","article-title":"Porphyromonas gingivalis in Alzheimer\u2019s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors","volume":"5","author":"Dominy","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.bbr.2013.06.015","article-title":"Tooth loss induces memory impairment and neuronal cell loss in APP transgenic mice","volume":"252","author":"Oue","year":"2013","journal-title":"Behav. Brain Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1111\/j.1532-5415.2012.04154.x","article-title":"Chewing ability and tooth loss: Association with cognitive impairment in an elderly population study","volume":"60","author":"Lexomboon","year":"2012","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.neubiorev.2010.06.002","article-title":"Mastication for the mind\u2014The relationship between mastication and cognition in ageing and dementia","volume":"35","author":"Weijenberg","year":"2011","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1267\/ahc.20-00036","article-title":"The Periodontium Damage Induces Neuronal Cell Death in the Trigeminal Mesencephalic Nucleus and Neurodegeneration in the Trigeminal Motor Nucleus in C57BL\/6J Mice","volume":"54","author":"Dhar","year":"2021","journal-title":"Acta Histochem. Cytochem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/0304-3940(87)90116-9","article-title":"Representation of tooth pulp in the mesencephalic trigeminal nucleus and the trigeminal ganglion in the cat, as revealed by retrogradely transported horseradish peroxidase","volume":"82","author":"Amano","year":"1987","journal-title":"Neurosci. Lett."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/S0099-2399(06)81568-2","article-title":"Effects of injury and inflammation on pulpal and periapical nerves","volume":"16","author":"Byers","year":"1990","journal-title":"J. Endod."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"839622","DOI":"10.3389\/fnins.2022.839622","article-title":"Tooth Loss Suppresses Hippocampal Neurogenesis and Leads to Cognitive Dysfunction in Juvenile Sprague-Dawley Rats","volume":"16","author":"Hu","year":"2022","journal-title":"Front. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"82","DOI":"10.3389\/fnagi.2017.00082","article-title":"Age-Related Difference in Functional Brain Connectivity of Mastication","volume":"9","author":"Lin","year":"2017","journal-title":"Front. Aging Neurosci."},{"key":"ref_70","first-page":"1540","article-title":"Reduced brain-derived neurotrophic factor expression in cortex and hippocampus involved in the learning and memory deficit in molarless SAMP8 mice","volume":"124","author":"Jiang","year":"2011","journal-title":"Chin. Med. J."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.neulet.2019.01.021","article-title":"Retrograde transport of masseter muscle-derived neprilysin to hippocampus","volume":"698","author":"Kobayashi","year":"2019","journal-title":"Neurosci. Lett."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"219","DOI":"10.3233\/ADR-180080","article-title":"Are Porphyromonas gingivalis outer membrane vesicles, microbullets for sporadic Alzheimer\u2019s disease manifestation?","volume":"20","author":"Singhrao","year":"2018","journal-title":"J. Alzheimers Dis. Rep."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s12987-020-00230-3","article-title":"A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity","volume":"17","author":"Kadry","year":"2020","journal-title":"Fluids Barriers CNS"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrn1824","article-title":"Astrocyte-endothelial interactions at the blood-brain barrier","volume":"7","author":"Abbott","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3677","DOI":"10.1242\/jcs.023887","article-title":"Tight junctions at a glance","volume":"121","author":"Balda","year":"2008","journal-title":"J. Cell Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1152\/physrev.00035.2003","article-title":"Endothelial cell-to-cell junctions: Molecular organization and role in vascular homeostasis","volume":"84","author":"Bazzoni","year":"2004","journal-title":"Physiol. Rev."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41586-020-2247-3","article-title":"APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline","volume":"581","author":"Montagne","year":"2020","journal-title":"Nature"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1148\/radiol.2016152244","article-title":"Blood-Brain Barrier Leakage in Patients with Early Alzheimer Disease","volume":"281","author":"Burgmans","year":"2016","journal-title":"Radiology"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"9187","DOI":"10.1523\/JNEUROSCI.20-24-09187.2000","article-title":"Differential expression of plasticity-related genes in waking and sleep and their regulation by the noradrenergic system","volume":"20","author":"Cirelli","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1146\/annurev.neuro.22.1.11","article-title":"The cell biology of the blood-brain barrier","volume":"22","author":"Rubin","year":"1999","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1046\/j.1471-4159.2001.00556.x","article-title":"Noradrenaline provides long-term protection to dopaminergic neurons by reducing oxidative stress","volume":"79","author":"Troadec","year":"2001","journal-title":"J. Neurochem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/j.neuroscience.2005.01.038","article-title":"Effects of low dose N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine administration on exploratory and amphetamine-induced behavior and dopamine D2 receptor function in rats with high or low exploratory activity","volume":"132","author":"Alttoa","year":"2005","journal-title":"Neuroscience"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1471-2202-6-31","article-title":"Co-release of noradrenaline and dopamine in the cerebral cortex elicited by single train and repeated train stimulation of the locus coeruleus","volume":"6","author":"Devoto","year":"2005","journal-title":"BMC Neurosci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s00441-004-0944-0","article-title":"Cellular pathology of Parkinson\u2019s disease: Astrocytes, microglia, and inflammation","volume":"318","author":"Teismann","year":"2004","journal-title":"Cell Tissue Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1046\/j.1471-4159.2002.00990.x","article-title":"Protective action of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of Parkinson\u2019s disease","volume":"82","author":"Breidert","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1111\/prd.12393","article-title":"The oral microbiome: Role of key organisms and complex networks in oral health and disease","volume":"87","author":"Sedghi","year":"2021","journal-title":"Periodontol. 2000"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1111\/j.1600-0757.2005.00113.x","article-title":"Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia: The \u201cred complex\u201d, a prototype polybacterial pathogenic consortium in periodontitis","volume":"38","author":"Holt","year":"2005","journal-title":"Periodontol. 2000"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1111\/j.1399-302X.1992.tb00589.x","article-title":"Demonstration of a bimodal coaggregation reaction between Porphyromonas gingivalis and Treponema denticola","volume":"7","author":"Grenier","year":"1992","journal-title":"Oral Microbiol. Immunol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1177\/00220345930720060601","article-title":"Stimulation of in vitro growth of Treponema denticola by extracellular growth factors produced by Porphyromonas gingivalis","volume":"72","author":"Nilius","year":"1993","journal-title":"J. Dent. Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1111\/j.1600-0765.1995.tb01284.x","article-title":"Distribution of Porphyromonas gingivalis and Treponema denticola in human subgingival plaque at different periodontal pocket depths examined by immunohistochemical methods","volume":"30","author":"Kigure","year":"1995","journal-title":"J. Periodontal Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1034\/j.1600-051X.1999.260711.x","article-title":"Inability of intact cells of Treponema denticola to degrade human serum proteins IgA, IgG and albumin","volume":"26","author":"Hollmann","year":"1999","journal-title":"J. Clin. Periodontol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1678","DOI":"10.1177\/00220345010800071501","article-title":"The Capacity of Porphyromonas gingivalis to Multiply Under Iron-limiting Conditions Correlates with its Pathogenicity in an Animal Model","volume":"80","author":"Grenier","year":"2001","journal-title":"J. Dent. Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/j.1600-0765.2005.00774.x","article-title":"Stimulation of growth of Porphyromonas gingivalis by cell extracts from Tannerella forsythia","volume":"40","author":"Yoneda","year":"2005","journal-title":"J. Periodontal. Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"432","DOI":"10.3389\/fcimb.2019.00432","article-title":"The Role of Treponema denticola Motility in Synergistic Biofilm Formation with Porphyromonas gingivalis","volume":"9","author":"Ng","year":"2019","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1034\/j.1600-0757.2002.03007.x","article-title":"Periodontal epithelium: A newly recognized role in health and disease","volume":"30","author":"Dale","year":"2002","journal-title":"Periodontol. 2000"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1111\/j.1600-0757.2005.00148.x","article-title":"Role of bacteria in health and disease of periodontal tissues","volume":"40","author":"Feng","year":"2006","journal-title":"Periodontol. 2000"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1111\/j.2041-1014.2012.00660.x","article-title":"The fate of Treponema denticola within human gingival epithelial cells","volume":"27","author":"Shin","year":"2012","journal-title":"Mol. Oral Microbiol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1128\/IAI.74.1.703-710.2006","article-title":"Intercellular spreading of Porphyromonas gingivalis infection in primary gingival epithelial cells","volume":"74","author":"Yilmaz","year":"2006","journal-title":"Infect. Immun."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1038\/icb.2011.85","article-title":"Toll-like receptor 9 mediates oral bacteria-induced, I.L.;-8 expression in gingival epithelial cells","volume":"90","author":"Kim","year":"2012","journal-title":"Immunol. Cell Biol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1111\/j.1600-0765.2007.00974.x","article-title":"Innate immune responses of gingival epithelial cells to non-periodontopathic and periodontopathic bacteria","volume":"42","author":"Ji","year":"2007","journal-title":"J. Periodontal Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1128\/IAI.00808-09","article-title":"Treponema denticola suppresses expression of human beta-defensin-3 in gingival epithelial cells through inhibition of TLR2 activation axis","volume":"78","author":"Shin","year":"2010","journal-title":"Infect. Immun."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"885","DOI":"10.2217\/fvl.12.81","article-title":"HSV, axonal transport and Alzheimer\u2019s disease: In vitro and in vivo evidence for causal relationships","volume":"7","author":"Bearer","year":"2012","journal-title":"Future Virol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1046\/j.1474-9728.2003.00069.x","article-title":"Fast anterograde transport of herpes simplex virus: Role for the amyloid precursor protein of Alzheimer\u2019s disease","volume":"2","author":"DeGiorgis","year":"2003","journal-title":"Aging Cell"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s002030100351","article-title":"Selenium-dependent growth of Treponema denticola: Evidence for a clostridial-type glycine reductase","volume":"177","author":"Rother","year":"2001","journal-title":"Arch. Microbiol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"5646","DOI":"10.1073\/pnas.0307639101","article-title":"Comparison of the genome of the oral pathogen Treponema denticola with other spirochete genomes","volume":"101","author":"Seshadri","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"19351","DOI":"10.1074\/jbc.M801034200","article-title":"A 52-kDa leucyl aminopeptidase from treponema denticola is a cysteinylglycinase that mediates the second step of glutathione metabolism","volume":"283","author":"Chu","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.resmic.2003.08.001","article-title":"Role of dentilisin in Treponema denticola epithelial cell layer penetration","volume":"154","author":"Chi","year":"2003","journal-title":"Res. Microbiol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1111\/j.1574-6968.1998.tb13047.x","article-title":"Mutagenesis of outer membrane virulence determinants of the oral spirochete Treponema denticola","volume":"163","author":"Fenno","year":"1998","journal-title":"FEMS Microbiol. Lett."},{"key":"ref_109","unstructured":"Radolf, J.D., and Lukehart, S.A. (2006). Virulence determinants of oral treponemes. Pathogenic Treponema, Caister Academic Press."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1099\/mic.0.28317-0","article-title":"Lipoprotein computational prediction in spirochaetal genomes","volume":"152","author":"Setubal","year":"2006","journal-title":"Microbiology"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1128\/iai.55.1.111-117.1987","article-title":"Functional characterization of extracellular vesicles produced by Bacteroides gingivalis","volume":"55","author":"Grenier","year":"1987","journal-title":"Infect. Immun."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1177\/0022034510385242","article-title":"Virulence factors of the oral spirochete Treponema denticola","volume":"90","author":"Dashper","year":"2011","journal-title":"J. Dent. Res."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.tins.2010.03.006","article-title":"Retrograde axonal transport: Pathways to cell death?","volume":"33","author":"Perlson","year":"2010","journal-title":"Trends Neurosci."},{"key":"ref_114","first-page":"220","article-title":"Electrophysiological dysfunction and cellular disruption of sensory neurones during incubation with Treponema Pallidum","volume":"58","author":"Oakes","year":"1982","journal-title":"Br. J. Vener. Dis."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1046\/j.0902-0055.2001.00100.x","article-title":"Molecular and immunological evidence of oral Treponema in the human brain and their association with Alzheimer\u2019s disease","volume":"17","author":"Riviere","year":"2002","journal-title":"Oral Microbiol. Immunol."},{"key":"ref_116","first-page":"407","article-title":"Treponema Pallidum in peripheral nerve tissue of syphilitic chancres","volume":"62","author":"Secher","year":"1982","journal-title":"Acta Dermatovener."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1007\/s12031-021-01827-5","article-title":"Oral Treponema denticola Infection Induces A\u03b21-40 and A\u03b21-42 Accumulation in the Hippocampus of C57BL\/6 Mice","volume":"71","author":"Su","year":"2021","journal-title":"J. Mol. Neurosci."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"195","DOI":"10.3389\/fnagi.2017.00195","article-title":"16S rRNA next generation sequencing analysis shows bacteria in Alzheimer\u2019s post-mortem brain. Front","volume":"20","author":"Emery","year":"2017","journal-title":"Aging Neurosci."},{"key":"ref_119","first-page":"3","article-title":"High throughput sequencing detects gingivitis and periodontal oral bacteria in Alzheimer\u2019s disease autopsy brains","volume":"1","author":"Siddiqui","year":"2019","journal-title":"J. Neurosci. Res."},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Pisani, F., Pisani, V., Arcangeli, F., Harding, A., and Singhrao, S.K. (2022). The Mechanistic Pathways of Periodontal Pathogens Entering the Brain: The Potential Role of Treponema denticola in Tracing Alzheimer\u2019s Disease Pathology. Int. J. Environ. Res. Public Health, 19.","DOI":"10.3390\/ijerph19159386"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/j.neuroscience.2010.06.009","article-title":"Locus coeruleus neuronal activity during the sleep-waking cycle in mice","volume":"169","author":"Takahashi","year":"2010","journal-title":"Neuroscience"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0079-6123(00)26013-5","article-title":"Locus coeruleus and regulation of behavioral flexibility and attention","volume":"126","author":"Rajkowski","year":"2000","journal-title":"Prog. Brain Res."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"6948","DOI":"10.1111\/ejn.15045","article-title":"Locus coeruleus in memory formation and Alzheimer\u2019s disease","volume":"54","author":"James","year":"2021","journal-title":"Eur. J. Neurosci."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"100284","DOI":"10.1016\/j.ynstr.2020.100284","article-title":"Anatomically and functionally distinct locus coeruleus efferents mediate opposing effects on anxiety-like behavior","volume":"13","author":"Borodovitsyna","year":"2020","journal-title":"Neurobiol. Stress"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"5","DOI":"10.3233\/JAD-210191","article-title":"The Locus Coeruleus in Aging and Alzheimer\u2019s Disease: A Postmortem and Brain Imaging Review","volume":"83","author":"Beardmore","year":"2021","journal-title":"J. Alzheimers Dis."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"173","DOI":"10.3233\/JAD-200385","article-title":"Oral Health Status in Subjects with Amnestic Mild Cognitive Impairment and Alzheimer\u2019s Disease: Data from the Zab\u00fat Aging Project","volume":"87","author":"Panzarella","year":"2022","journal-title":"J. Alzheimers Dis."},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Ide, M., Harris, M., Stevens, A., Sussams, R., Hopkins, V., Culliford, D., Fuller, J., Ibbett, P., Raybould, R., and Thomas, R. (2016). Periodontitis and Cognitive Decline in Alzheimer\u2019s Disease. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0151081"},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Kim, J.H., Oh, J.K., Wee, J.H., Kim, Y.H., Byun, S.H., and Choi, H.G. (2021). Association between Tooth Loss and Alzheimer\u2019s Disease in a Nested Case-Control Study Based on a National Health Screening Cohort. J. Clin. Med., 10.","DOI":"10.3390\/jcm10173763"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1007\/s00508-020-01638-5","article-title":"Knock-on effect of periodontitis to the pathogenesis of Alzheimer\u2019s disease?","volume":"132","author":"Leblhuber","year":"2020","journal-title":"Wien. Klin. Wochenschr."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1002\/alz.12378","article-title":"Effect of periodontal treatment on preclinical Alzheimer\u2019s disease\u2014Results of a trial emulation approach","volume":"18","author":"Schwahn","year":"2022","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"130","DOI":"10.3389\/fnana.2017.00130","article-title":"Trigeminal, Visceral and Vestibular Inputs May Improve Cognitive Functions by Acting through the Locus Coeruleus and the Ascending Reticular Activating System: A New Hypothesis","volume":"11","author":"Cataldo","year":"2018","journal-title":"Front. Neuroanat."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1136\/jnnp-2022-329136","article-title":"Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer\u2019s disease: Systematic review and meta-analysis","volume":"93","author":"David","year":"2022","journal-title":"J. Neurol. Neurosurg. Psychiatry"}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/20\/2\/1007\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:00:30Z","timestamp":1760119230000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/20\/2\/1007"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,5]]},"references-count":132,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["ijerph20021007"],"URL":"https:\/\/doi.org\/10.3390\/ijerph20021007","relation":{},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,5]]}}}