{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T03:08:56Z","timestamp":1792120136221,"version":"4.4.0"},"reference-count":49,"publisher":"Wiley","issue":"S1","license":[{"start":{"date-parts":[[2023,6,8]],"date-time":"2023-06-08T00:00:00Z","timestamp":1686182400000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aims<\/jats:title><jats:p>White matter lesions (WMLs) are involved in the pathological processes leading to cognitive decline and dementia. We examined the mechanisms underlying the exacerbation of ischemia\u2010induced cognitive impairment and WMLs by diet\u2010induced obesity, including lipopolysaccharide (LPS)\u2010triggered neuroinflammation via toll\u2010like receptor (TLR) 4.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Wild\u2010type (WT) and TLR4\u2010knockout (KO) C57BL\/6 mice were fed a high\u2010fat diet (HFD) or low\u2010fat diet (LFD), and subjected to bilateral carotid artery stenosis (BCAS). Diet groups were compared for changes in gut microbiota, intestinal permeability, systemic inflammation, neuroinflammation, WML severity, and cognitive dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In WT mice, HFD induced obesity and increased cognitive impairment and WML severity compared with LFD\u2010fed mice following BCAS. HFD caused gut dysbiosis and increased intestinal permeability, and plasma LPS and pro\u2010inflammatory cytokine concentrations. Furthermore, HFD\u2010fed mice had higher LPS levels and higher neuroinflammatory status, including increased TLR4 expression, in WMLs. In TLR4\u2010KO mice, HFD also caused obesity and gut dysbiosis but did not increase cognitive impairment or WML severity after BCAS. No difference was found between HFD\u2010 and LFD\u2010fed KO mice for LPS levels or inflammatory status in either plasma or WMLs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Inflammation triggered by LPS\u2013TLR4 signaling may mediate obesity\u2010associated exacerbation of cognitive impairment and WMLs from brain ischemia.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.14301","type":"journal-article","created":{"date-parts":[[2023,6,8]],"date-time":"2023-06-08T07:31:51Z","timestamp":1686209511000},"page":"200-212","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Microbial lipopolysaccharide\u2010induced inflammation contributes to cognitive impairment and white matter lesion progression in diet\u2010induced obese mice with chronic cerebral hypoperfusion"],"prefix":"10.1111","volume":"29","author":[{"given":"Toshiki","family":"Inaba","sequence":"first","affiliation":[{"name":"Department of Neurology Juntendo University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuo","family":"Yamashiro","sequence":"additional","affiliation":[{"name":"Department of Neurology Juntendo University School of Medicine  Tokyo Japan"},{"name":"Department of Neurology Juntendo University Urayasu Hospital  Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naohide","family":"Kurita","sequence":"additional","affiliation":[{"name":"Department of Neurology Juntendo University School of Medicine  Tokyo Japan"},{"name":"Department of Neurology Juntendo University Urayasu Hospital  Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Ueno","sequence":"additional","affiliation":[{"name":"Department of Neurology Juntendo University School of Medicine  Tokyo Japan"},{"name":"Department of Neurology University of Yamanashi  Yamanashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobukazu","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Department of Neurology Juntendo University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichiro","family":"Hira","sequence":"additional","affiliation":[{"name":"Department of Neurology Juntendo University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sho","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Department of Neurology Juntendo University School of Medicine  Tokyo Japan"},{"name":"Department of Neurology University of Yamanashi  Yamanashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chikage","family":"Kijima","sequence":"additional","affiliation":[{"name":"Department of Neurology Juntendo University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryohei","family":"Nakaguro","sequence":"additional","affiliation":[{"name":"Metagen Inc.  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