Leon M. Tai<\/a><\/p>\n\n\n\nAbstract<\/h2>\n\n\n\nBackground<\/h3>\n\n\n\n
APOE<\/em> genotype is the greatest genetic risk factor for sporadic Alzheimer\u2019s disease (AD). APOE4<\/em> increases AD risk up to 12-fold compared to APOE3<\/em>, an effect that is greater in females. Evidence suggests that one-way APOE<\/em> could modulate AD risk and progression through neuroinflammation. Indeed, APOE4<\/em> is associated with higher glial activation and cytokine levels in AD patients and mice. Therefore, identifying pathways that contribute to APOE4<\/em>-associated neuroinflammation is an important approach for understanding and treating AD. Human and in vivo evidence suggests that TLR4, one of the key receptors involved in the innate immune system, could be involved in APOE<\/em>-modulated neuroinflammation. Consistent with that idea, we previously demonstrated that the TLR4 antagonist IAXO-101 can reduce LPS- and A\u03b2-induced cytokine secretion in APOE4<\/em> glial cultures. Therefore, the goal of this study was to advance these findings and determine whether IAXO-101 can modulate neuroinflammation, A\u03b2 pathology, and behavior in mice that express APOE4<\/em>.<\/p>\n\n\n\nMethods<\/h3>\n\n\n\n
We used mice that express five familial AD mutations and human APOE3<\/em> (E3FAD) or APOE4<\/em> (E4FAD). Female and male E4FAD mice and female E3FAD mice were treated with vehicle or IAXO-101 in two treatment paradigms: prevention from 4 to 6 months of age or reversal from 6 to 7 months of age. Learning and memory were assessed by modified Morris water maze. A\u03b2 deposition, fibrillar amyloid deposition, astrogliosis, and microgliosis were assessed by immunohistochemistry. Soluble levels of A\u03b2 and apoE, insoluble levels of apoE and A\u03b2, and IL-1\u03b2 were measured by ELISA.<\/p>\n\n\n\nResults<\/h3>\n\n\n\n
IAXO-101 treatment resulted in lower Iba-1 coverage, lower number of reactive microglia, and improved memory in female E4FAD mice in both prevention and reversal paradigms. IAXO-101-treated male E4FAD mice also had lower Iba-1 coverage and reactivity in the RVS paradigm, but there was no effect on behavior. There was also no effect of IAXO-101 treatment on neuroinflammation and behavior in female E3FAD mice.<\/p>\n\n\n\n
Conclusion<\/h3>\n\n\n\n
Our data supports that TLR4 is a potential mechanistic therapeutic target for modulating neuroinflammation and cognition in APOE4<\/em> females.<\/p>\n","protected":false},"excerpt":{"rendered":"A small-molecule TLR4 antagonist reduced neuroinflammation in female E4FAD mice Deebika Balu,\u00a0Ana C. Valencia-Olvera,\u00a0Austin Nguyen,\u00a0Mehul Patnam,\u00a0Jason York,\u00a0Francesco Peri,\u00a0Frank Neumann,\u00a0Mary Jo LaDu\u00a0&\u00a0Leon M. Tai Abstract Background APOE genotype is the greatest genetic risk factor for sporadic Alzheimer\u2019s disease (AD). APOE4 increases AD risk up to 12-fold compared to APOE3, an effect that is greater in<\/p>\n
Read More<\/a><\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_jetpack_memberships_contains_paid_content":false,"footnotes":""},"categories":[5],"tags":[23,11],"class_list":["post-623","post","type-post","status-publish","format-standard","hentry","category-literature","tag-iaxo-101","tag-tlr4"],"yoast_head":"\n2023 A small-molecule TLR4 antagonist reduced neuroinflammation in female E4FAD mice - Innaxon Therapeutics<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/admin.innaxon.com\/index.php\/2023\/12\/18\/2023-a-small-molecule-tlr4-antagonist-reduced-neuroinflammation-in-female-e4fad-mice\/\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"2023 A small-molecule TLR4 antagonist reduced neuroinflammation in female E4FAD mice - Innaxon Therapeutics\" \/>\n<meta property=\"og:description\" content=\"A small-molecule TLR4 antagonist reduced neuroinflammation in female E4FAD mice Deebika Balu,\u00a0Ana C. 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