{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:38:59Z","timestamp":1790771939766,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2020,7,6]],"date-time":"2020-07-06T00:00:00Z","timestamp":1593993600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Alzheimer's disease (AD) patients and transgenic mice have beta\u2010amyloid (A\u03b2) aggregation in the gastrointestinal (GI) tract.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>It is possible that A\u03b2 from the periphery contributes to the load of A\u03b2 in the brain, as A\u03b2 has prion\u2010like properties.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The present investigations demonstrate that A\u03b2 injected into the GI tract of ICR mice is internalised into enteric cholinergic neurons; at 1 month, administration of A\u03b2 into the body of the stomach and the proximal colon was observed to partly redistribute to the fundus and jejunum; at 1 year, vagal and cerebral \u03b2\u2010amyloidosis was present, and mice exhibited GI dysfunction and cognitive deficits.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These data reveal a previously undiscovered mechanism that potentially contributes to the development of AD.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Alzheimer's disease (AD) is the most common age\u2010related cause of dementia, characterised by extracellular beta\u2010amyloid (A\u03b2) plaques and intracellular phosphorylated tau tangles in the brain. A\u03b2 deposits have also been observed in the gastrointestinal (GI) tract of AD patients and transgenic mice, with overexpression of amyloid precursor protein. In the present studies, we investigate whether intra\u2010GI administration of A\u03b2 can potentially induce amyloidosis in the central nervous system (CNS) and AD\u2010related pathology such as dementia. We micro\u2010injected A\u03b21\u201342 oligomers (4\u00a0\u03bcg per site, five sites) or vehicle (saline, 5\u00a0\u03bcl) into the gastric wall of ICR mice under general anaesthesia. Immunofluorescence staining and <jats:italic>in vivo<\/jats:italic> imaging showed that HiLyte Fluor 555\u2010labelled A\u03b21\u201342 had migrated within 3\u00a0h via the submucosa to nearby areas and was internalised into cholinergic neurons. At 1 month, HiLyte Fluor 555\u2010labelled A\u03b21\u201342 in the body of the stomach and proximal colon had partly re\u2010distributed to the fundus and jejunum. At 1 year, the jejunum showed functional alterations in neuromuscular coupling (<jats:italic>P\u00a0<\/jats:italic>&lt;\u00a00.001), and A\u03b2 deposits were present in the vagus and brain, with animals exhibiting cognitive impairments in the Y\u2010maze spontaneous alteration test (<jats:italic>P\u00a0<\/jats:italic>&lt;\u00a00.001) and the novel object recognition test (<jats:italic>P\u00a0<\/jats:italic>&lt;\u00a00.001). We found that enteric A\u03b2 oligomers induce an alteration in gastric function, amyloidosis in the CNS, and AD\u2010like dementia via vagal mechanisms. Our results suggest that A\u03b2 load is likely to occur initially in the GI tract and may translocate to the brain, opening the possibility of new strategies for the early diagnosis and prevention of AD.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp279919","type":"journal-article","created":{"date-parts":[[2020,7,3]],"date-time":"2020-07-03T01:15:30Z","timestamp":1593738930000},"page":"4209-4223","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":118,"title":["Intra\u2010gastrointestinal amyloid\u2010\u03b21\u201342 oligomers perturb enteric function and induce Alzheimer's disease pathology"],"prefix":"10.1113","volume":"598","author":[{"given":"Yayi","family":"Sun","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nerina R.","family":"Sommerville","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0031-0151","authenticated-orcid":false,"given":"Julia Yuen Hang","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man Piu","family":"Ngan","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8933-7600","authenticated-orcid":false,"given":"Daniel","family":"Poon","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene D.","family":"Ponomarev","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3336-894X","authenticated-orcid":false,"given":"Zengbing","family":"Lu","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0895-9182","authenticated-orcid":false,"given":"Jeng S. C.","family":"Kung","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8316-0792","authenticated-orcid":false,"given":"John A.","family":"Rudd","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences"},{"name":"Faculty of Medicine the Laboratory Animal Services Centre The Chinese University of Hong Kong  New Territories Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,7,6]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.3988\/jcn.2011.7.1.1"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2005.11.012"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-160926"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12397"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2015.06.047"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/alzrt269"},{"key":"e_1_2_5_8_1","first-page":"142","article-title":"The \u2018Verbal study and memory test\u2019 (VLMT) \u2010 Qualification and norms for the early and differential diagnostics of the Alzheimer\u2010dementia","volume":"78","author":"Eisele EE","year":"2007","journal-title":"Nervenarzt"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-015-1516-y"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2015.00245"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2010.04.003"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep09226"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-014-1343-6"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2008.05866.x"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2012.04.039"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.73.4.371"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1431"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00069a001"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90635-4"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature15369"},{"issue":"6","key":"e_1_2_5_21_1","first-page":"427","article-title":"Interactions between beta\u2010amyloid and central cholinergic neurons: Implications for Alzheimer's disease","volume":"29","author":"Kar S","year":"2004","journal-title":"J Psychiatry Neurosci"},{"issue":"109","key":"e_1_2_5_22_1","article-title":"Intracerebroventricular injection of Amyloid\u2010\u03b2 peptides in normal mice to acutely induce alzheimer\u2010like cognitive deficits","volume":"2016","author":"Kim HY","year":"2016","journal-title":"J Vis Exp"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19113573"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2009.06873.x"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.03862.x"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2010-101263"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bios.2009.06.006"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2012.07.024"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14547"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-1331.2008.02056.x"},{"key":"e_1_2_5_31_1","article-title":"Gastrointestinal dysfunctions in Parkinson's disease: Symptoms and treatments","volume":"2016","author":"Poirier AA","year":"2016","journal-title":"Parkinsons Dis"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-1331.2008.02057.x"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11481-011-9327-y"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1590\/S0100-879X2002000100014"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2010.11.058"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2018.02.022"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-120511"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24518"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24448"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1159\/000484409"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1186\/2051-5960-1-2"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2019.00107"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2015.06.015"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1408900111"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2014.00088"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0147733"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/648740"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2FJP279919","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP279919","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP279919","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP279919","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T01:26:20Z","timestamp":1693358780000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP279919"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,6]]},"references-count":46,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2020,10]]}},"alternative-id":["10.1113\/JP279919"],"URL":"https:\/\/doi.org\/10.1113\/jp279919","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,6]]},"assertion":[{"value":"2020-04-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-06-12","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-07-06","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}