{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T07:05:30Z","timestamp":1792652730779,"version":"4.5.0"},"reference-count":34,"publisher":"National Academy of Sciences","issue":"15","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,4,13]]},"abstract":"<jats:p>\n                    Recent epidemiological studies suggest that diabetes mellitus is a strong risk factor for Alzheimer disease. However, the underlying mechanisms remain largely unknown. In this study, to investigate the pathophysiological interaction between these diseases, we generated animal models that reflect the pathologic conditions of both diseases. We crossed Alzheimer transgenic mice (APP23) with two types of diabetic mice (\n                    <jats:italic>ob<\/jats:italic>\n                    \/\n                    <jats:italic>ob<\/jats:italic>\n                    and NSY mice), and analyzed their metabolic and brain pathology. The onset of diabetes exacerbated Alzheimer-like cognitive dysfunction without an increase in brain amyloid-\u03b2 burden in double-mutant (APP\n                    <jats:sup>+<\/jats:sup>\n                    -\n                    <jats:italic>ob<\/jats:italic>\n                    \/\n                    <jats:italic>ob<\/jats:italic>\n                    ) mice. Notably, APP\n                    <jats:sup>+<\/jats:sup>\n                    -\n                    <jats:italic>ob<\/jats:italic>\n                    \/\n                    <jats:italic>ob<\/jats:italic>\n                    mice showed cerebrovascular inflammation and severe amyloid angiopathy. Conversely, the cross-bred mice showed an accelerated diabetic phenotype compared with\n                    <jats:italic>ob<\/jats:italic>\n                    \/\n                    <jats:italic>ob<\/jats:italic>\n                    mice, suggesting that Alzheimer amyloid pathology could aggravate diabetes. Similarly, APP\n                    <jats:sup>+<\/jats:sup>\n                    -NSY fusion mice showed more severe glucose intolerance compared with diabetic NSY mice. Furthermore, high-fat diet feeding induced severe memory deficits in APP\n                    <jats:sup>+<\/jats:sup>\n                    -NSY mice without an increase in brain amyloid-\u03b2 load. Here, we created Alzheimer mouse models with early onset of cognitive dysfunction. Cerebrovascular changes and alteration in brain insulin signaling might play a pivotal role in this relationship. These findings could provide insights into this intensely debated association.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1000645107","type":"journal-article","created":{"date-parts":[[2010,3,15]],"date-time":"2010-03-15T23:59:34Z","timestamp":1268697574000},"page":"7036-7041","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":457,"title":["Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and A\u03b2 deposition in an Alzheimer mouse model with diabetes"],"prefix":"10.1073","volume":"107","author":[{"given":"Shuko","family":"Takeda","sequence":"first","affiliation":[{"name":"Departments of aClinical Gene Therapy and"},{"name":"Geriatric Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoyuki","family":"Sato","sequence":"additional","affiliation":[{"name":"Departments of aClinical Gene Therapy and"},{"name":"Geriatric Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kozue","family":"Uchio-Yamada","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Animal Models, National Institute of Biomedical Innovation, Osaka 567-0085, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoko","family":"Sawada","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Animal Models, National Institute of Biomedical Innovation, Osaka 567-0085, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanori","family":"Kunieda","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Animal Models, National Institute of Biomedical Innovation, Osaka 567-0085, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Departments of aClinical Gene Therapy and"},{"name":"Geriatric Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitomi","family":"Kurinami","sequence":"additional","affiliation":[{"name":"Departments of aClinical Gene Therapy and"},{"name":"Geriatric Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuru","family":"Shinohara","sequence":"additional","affiliation":[{"name":"Departments of aClinical Gene Therapy and"},{"name":"Geriatric Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromi","family":"Rakugi","sequence":"additional","affiliation":[{"name":"Geriatric Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuichi","family":"Morishita","sequence":"additional","affiliation":[{"name":"Departments of aClinical Gene Therapy and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2010,3,15]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)01081-X"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1586\/ern.09.18"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.53.9.1937"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072994"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(02)02037-0"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01640"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2005.01.004"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.03-0978fje"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2990.2008.00948.x"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000247053.45483.4e"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1387"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.12.7.871"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm890"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600415"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.24.13287"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/s001250051472"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.108.536839"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.287.19.2570"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jcbfm.9600082"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.04.014"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0308724101"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.109.188516"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/syn.20644"},{"key":"e_1_3_3_24_2","first-page":"1005","article-title":"Inflammation in Alzheimer disease: driving force, bystander or beneficial response?","volume":"12","author":"Wyss-Coray T","year":"2006","unstructured":"T Wyss-Coray, Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 12, 1005\u20131015 (2006).","journal-title":"Nat Med"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.011015"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2005.08.021"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1080\/01688639208402827"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-3223(91)90158-I"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1104344"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1126010"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.06-7703com"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2009.05.037"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2008.12.004"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.52.2.227"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1000645107","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T19:03:54Z","timestamp":1649790234000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1000645107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,3,15]]},"references-count":34,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2010,4,13]]}},"alternative-id":["10.1073\/pnas.1000645107"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1000645107","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.2820960.2486058","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,3,15]]},"assertion":[{"value":"2010-03-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}