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LPS levels increase with brain aging and accumulate around neurons in Alzheimer\u2019s disease (AD) brains. Microbiome-generated LPS and other endotoxins cross gut barriers, enter systemic circulation, and translocate across the blood\u2013brain barrier into vascularized brain regions. These processes are exacerbated by aging and neurovascular diseases. Although pro-homeostatic systems mitigate LPS effects, these defenses can fail. This study provides the first evidence that acyloxyacyl hydrolase (AOAH; EC 3.1.1.77), a microglia-enriched LPS detoxifying enzyme, shows reduced expression in AD brain tissue. Analysis of AD patient brains revealed reduced AOAH messenger RNA (mRNA) levels, accompanied by elevated expression of microRNA (hsa-miR-450b-5p), an inflammation regulator. Furthermore, luciferase reporter assays demonstrated that miR-450b-5p specifically targets the AOAH 3\u2032-UTR, leading to a dose-dependent suppression of reporter activity. Also, in vitro experiments on human neuronal glial (HNG) cells further confirmed down-regulation of AOAH expression at protein levels by miR-450b-5p. These findings suggest miR-450b-5p-mediated AOAH deficiency drives LPS-associated neurotoxicity and inflammatory neurodegeneration in AD.<\/jats:p>","DOI":"10.3390\/molecules31030486","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T11:09:22Z","timestamp":1769771362000},"page":"486","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Down-Regulation of Acyloxyacyl Hydrolase Expression in Alzheimer\u2019s Disease Impairs LPS Detoxification and Contributes to Brain Pro-Inflammatory Signaling"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3014-2405","authenticated-orcid":false,"given":"Yuhai","family":"Zhao","sequence":"first","affiliation":[{"name":"Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan M.","family":"Sharfman","sequence":"additional","affiliation":[{"name":"Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian R.","family":"Jaber","sequence":"additional","affiliation":[{"name":"Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7983-5275","authenticated-orcid":false,"given":"Christopher M.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology & Parasitology, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter J.","family":"Lukiw","sequence":"additional","affiliation":[{"name":"Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9243-5444","authenticated-orcid":false,"given":"Nicolas G.","family":"Bazan","sequence":"additional","affiliation":[{"name":"Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.nutres.2023.02.007","article-title":"The Microbiome as a Major Function of the Gastrointestinal Tract and Its Implication in Micronutrient Metabolism and Chronic Diseases","volume":"112","author":"Lin","year":"2023","journal-title":"Nutr. 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