{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T11:02:06Z","timestamp":1787655726499,"version":"build-2736575974"},"reference-count":32,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2019,6,29]],"date-time":"2019-06-29T00:00:00Z","timestamp":1561766400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Preventive approaches for age-related memory decline and dementia have become a high priority in the aging society because of the lack of therapeutic approaches. Recent epidemiological studies have reported that fermented dairy products can help prevent dementia. Previously, we identified tryptophan\u2013tyrosine (WY) and tryptophan\u2013methionine (WM) peptides as the suppressants of activation of the primary microglia and showed that WY peptide consumption suppresses inflammation in the brains of Alzheimer\u2019s disease model mice. However, the effects of the WM peptide on inflammation in the brain and Alzheimer\u2019s pathology have not been investigated. Here, we evaluated the effect of WM peptide consumption on Alzheimer\u2019s disease model (5\u00d7FAD) mice. In 5\u00d7FAD mice, intake of WM peptide suppressed the production of inflammatory cytokines, activation of microglia, and infiltration of activated microglia around \u03b2 amyloid (A\u03b2) depositions. WM peptide intake reduced A\u03b2 deposition in the cortex and hippocampus and then improved the object recognition memory. Taken together with previous reports, the current findings indicate that ingestion of tryptophan-related peptides or food material rich in tryptophan-related peptides, thereby regulating microglial activity, represents a potential preventive approach for cognitive decline and dementia related to inflammation.<\/jats:p>","DOI":"10.3390\/ijms20133206","type":"journal-article","created":{"date-parts":[[2019,7,1]],"date-time":"2019-07-01T03:23:59Z","timestamp":1561951439000},"page":"3206","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Preventive Effects of Tryptophan\u2013Methionine Dipeptide on Neural Inflammation and Alzheimer\u2019s Pathology"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5957-8710","authenticated-orcid":false,"given":"Yasuhisa","family":"Ano","sequence":"first","affiliation":[{"name":"Graduate School of Agricultural and Life Sciences, the University of Tokyo, Tokyo 113-8657, Japan"},{"name":"Research Laboratories for Health Science &amp; Food Technologies, Kirin Holdings Co. Ltd., Kanagawa 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Yoshino","sequence":"additional","affiliation":[{"name":"Graduate School of Agricultural and Life Sciences, the University of Tokyo, Tokyo 113-8657, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuyuki","family":"Uchida","sequence":"additional","affiliation":[{"name":"Graduate School of Agricultural and Life Sciences, the University of Tokyo, Tokyo 113-8657, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Graduate School of Agricultural and Life Sciences, the University of Tokyo, Tokyo 113-8657, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"311","DOI":"10.3233\/JAD-2010-1221","article-title":"Alzheimer\u2019s disease and the amyloid-\u03b2 peptide","volume":"19","author":"Murphy","year":"2010","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"729","DOI":"10.3233\/JAD-2009-1090","article-title":"Amyloid-\u03b2, tau, and dementia","volume":"17","author":"Takashima","year":"2009","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"978","DOI":"10.3389\/fneur.2018.00978","article-title":"Microglia in Alzheimer\u2019s Disease: Risk Factors and Inflammation","volume":"9","author":"Katsumoto","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_4","first-page":"575","article-title":"Inflammation as a central mechanism in Alzheimer\u2019s disease","volume":"4","author":"Kinney","year":"2018","journal-title":"Alz. Dement."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/1742-2094-7-56","article-title":"LPS- induced inflammation exacerbates phospho-tau pathology in rTg4510 mice","volume":"7","author":"Lee","year":"2010","journal-title":"J. Neuroinflamm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1111\/imm.12922","article-title":"Inflammation in CNS neurodegenerative diseases","volume":"154","author":"Stephenson","year":"2018","journal-title":"Immunology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3240","DOI":"10.1172\/JCI90606","article-title":"Microglia in Alzheimer\u2019s disease","volume":"127","author":"Sarlus","year":"2017","journal-title":"J. Clin. Invest."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Ano, Y., and Nakayama, H. (2018). Preventive Effects of Dairy Products on Dementia and the Underlying Mechanisms. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19071927"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1017\/S0007114511000158","article-title":"Dairy constituents and neurocognitive health in ageing","volume":"106","author":"Camfield","year":"2011","journal-title":"Br. J. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.3945\/ajcn.112.045575","article-title":"Dietary patterns and risk of dementia in an elderly Japanese population: The Hisayama Study","volume":"97","author":"Ozawa","year":"2013","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1111\/jgs.12887","article-title":"Milk and dairy consumption and risk of dementia in an elderly Japanese population: The Hisayama Study","volume":"62","author":"Ozawa","year":"2014","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.clnu.2015.03.023","article-title":"Association between intake of dairy products and short-term memory with and without adjustment for genetic and family environmental factors: A twin study","volume":"35","author":"Ogata","year":"2016","journal-title":"Clin. Nutr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"399","DOI":"10.3389\/fnins.2019.00399","article-title":"Supplementation with Whey Peptide Rich in \u03b2-Lactolin Improves Cognitive Performance in Healthy Older Adults: A Randomized, Double-Blind, Placebo-Controlled Study","volume":"13","author":"Kita","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ano, Y., Ozawa, M., Kutsukake, T., Sugiyama, S., Uchida, K., Yoshida, A., and Nakayama, H. (2015). Preventive effects of a fermented dairy product against Alzheimer\u2019s disease and identification of a novel oleamide with enhanced microglial phagocytosis and anti-inflammatory activity. PloS ONE, 10.","DOI":"10.1371\/journal.pone.0118512"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ano, Y., Yoshino, Y., Kutsukake, T., Ohya, R., Fukuda, T., Uchida, K., Takashima, A., and Nakayama, H. (2019). Tryptophan-related dipeptides in fermented dairy products suppress microglial activation and prevent cognitive decline. Aging.","DOI":"10.18632\/aging.101909"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2502","DOI":"10.1038\/ncomms3502","article-title":"Analysing the substrate multispecificity of a proton-coupled oligopeptide transporter using a dipeptide library","volume":"4","author":"Ito","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ano, Y., Ayabe, T., Ohya, R., Kondo, K., Kitaoka, S., and Furuyashiki, T. (2019). Tryptophan-Tyrosine Dipeptide, the Core Sequence of \u03b2-Lactolin, Improves Memory by Modulating the Dopamine System. Nutrients, 11.","DOI":"10.3390\/nu11020348"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.neurobiolaging.2018.07.016","article-title":"Novel lactopeptides in fermented dairy products improve memory function and cognitive decline","volume":"72","author":"Ano","year":"2018","journal-title":"Neurobiol. Aging"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Nagatsu, T., and Sawada, M. (2006). Molecular mechanism of the relation of monoamine oxidase B and its inhibitors to Parkinson\u2019s disease: Possible implications of glial cells. J. Neural. Trans. Suppl., 53\u201365.","DOI":"10.1007\/978-3-211-33328-0_7"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"21986","DOI":"10.1038\/srep21986","article-title":"Inhibitory effect of traditional oriental medicine-derived monoamine oxidase B inhibitor on radioresistance of non-small cell lung cancer","volume":"6","author":"Son","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1186\/1742-2094-8-153","article-title":"Effects of betaine on lipopolysaccharide-induced memory impairment in mice and the involvement of GABA transporter 2","volume":"8","author":"Miwa","year":"2011","journal-title":"J. Neuroinflamm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s12974-014-0220-5","article-title":"Spermine reverses lipopolysaccharide-induced memory deficit in mice","volume":"12","author":"Fruhauf","year":"2015","journal-title":"J. Neuroinflamm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1093\/brain\/awx120","article-title":"Brain inflammation accompanies amyloid in the majority of mild cognitive impairment cases due to Alzheimer\u2019s disease","volume":"140","author":"Parbo","year":"2017","journal-title":"Brain J. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Imbimbo, B.P., Solfrizzi, V., and Panza, F. (2010). Are NSAIDs useful to treat Alzheimer\u2019s disease or mild cognitive impairment?. Front. Aging Neurosci., 2.","DOI":"10.3389\/fnagi.2010.00019"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1212\/WNL.48.3.626","article-title":"Risk of Alzheimer\u2019s disease and duration of NSAID use","volume":"48","author":"Stewart","year":"1997","journal-title":"Neurology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3720","DOI":"10.1074\/jbc.M116.763813","article-title":"Iso-\u03b1-acids, Bitter Components of Beer, Prevent Inflammation and Cognitive Decline Induced in a Mouse Model of Alzheimer\u2019s Disease","volume":"292","author":"Ano","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"16","DOI":"10.3389\/fnagi.2019.00016","article-title":"Iso-\u03b1-acids, Hop-Derived Bitter Components of Beer, Attenuate Age-Related Inflammation and Cognitive Decline","volume":"11","author":"Ano","year":"2019","journal-title":"Front. Aging Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"81","DOI":"10.3389\/fphar.2019.00081","article-title":"Iso-\u03b1-Acids, Bitter Components in Beer, Suppress Inflammatory Responses and Attenuate Neural Hyperactivation in the Hippocampus","volume":"10","author":"Ano","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ano, Y., Takaichi, Y., Uchida, K., Kondo, K., Nakayama, H., and Takashima, A. (2018). Iso-\u03b1-Acids, the Bitter Components of Beer, Suppress Microglial Inflammation in rTg4510 Tauopathy. Molecules, 23.","DOI":"10.3390\/molecules23123133"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/S0014-5793(00)02076-7","article-title":"Regulation of APP cleavage by \u03b1-, \u03b2- and \u03b3-secretases","volume":"483","author":"Nunan","year":"2000","journal-title":"FEBS Lett."},{"key":"ref_31","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_32","doi-asserted-by":"crossref","unstructured":"Ano, Y., Hoshi, A., Ayabe, T., Ohya, R., Uchida, S., Yamada, K., Kondo, K., Kitaoka, S., and Furuyashiki, T. (2019). Iso-\u03b1-acids, the bitter components of beer, improve hippocampus-dependent memory through vagus nerve activation. FASEB J.","DOI":"10.1096\/fj.201801868RR"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/13\/3206\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:02:25Z","timestamp":1760187745000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/13\/3206"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,29]]},"references-count":32,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2019,7]]}},"alternative-id":["ijms20133206"],"URL":"https:\/\/doi.org\/10.3390\/ijms20133206","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,29]]}}}