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Clinically available drugs mainly target acetylcholinesterase (AChE) and indirectly sustain cholinergic neuronal tonus. Butyrylcholinesterase (BChE) also controls acetylcholine (ACh) turnover and is involved in the formation of A\u00df aggregates and senile plaques. UW\u2010MD\u201095 is a novel carbamate\u2010based compound acting as a potent pseudo\u2010irreversible BChE inhibitor, with high selectivity versus AChE, and showing promising protective potentials in AD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We characterized the neuroprotective activity of UW\u2010MD\u201095 in mice treated intracerebroventricularly with oligomerized A\u03b2<jats:sub>25\u201035<\/jats:sub> peptide using behavioral, biochemical, and immunohistochemical approaches.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>When injected acutely 30\u2009min before the behavioral tests (spontaneous alternation in the Y\u2010maze, object recognition, or passive avoidance), UW\u2010MD\u201095 (0.3\u20103\u2009mg\/kg) showed anti\u2010amnesic effects in A\u03b2<jats:sub>25\u201035<\/jats:sub>\u2010treated mice. When injected once a day over 7\u2009days, it prevented A\u03b2<jats:sub>25\u201035<\/jats:sub>\u2010induced memory deficits. This effect was lost in BChE knockout mice. Moreover, the compound prevented A\u03b2<jats:sub>25\u201035<\/jats:sub>\u2010induced oxidative stress (assessed by lipid peroxidation or cytochrome c release), neuroinflammation (IL\u20106 and TNF\u03b1 levels or GFAP and IBA1 immunoreactivity) in the hippocampus and cortex, and apoptosis (Bax level). Moreover, UW\u2010MD\u201095 significantly reduced the increase in soluble A\u03b2<jats:sub>1\u201042<\/jats:sub> level in the hippocampus induced by A\u03b2<jats:sub>25\u201035<\/jats:sub>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>UW\u2010MD\u201095 appeared as a potent neuroprotective compound in the A\u03b2<jats:sub>25\u201035<\/jats:sub> model of AD, with potentially an impact on A\u03b2<jats:sub>1\u201042<\/jats:sub> accumulation that could suggest a novel mechanism of neuroprotection.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.14814","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T06:45:10Z","timestamp":1718693110000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["The selective butyrylcholinesterase inhibitor UW\u2010MD\u201095 shows symptomatic and neuroprotective effects in a pharmacological mouse model of Alzheimer's disease"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4639-2244","authenticated-orcid":false,"given":"Allison","family":"Carles","sequence":"first","affiliation":[{"name":"MMDN, Univ Montpellier, INSERM, EPHE  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Pharmazeutische und Medizinische Chemie Institut f\u00fcr Pharmazie und Lebensmittelchemie, Julius\u2010Maximilians\u2010Universit\u00e4t W\u00fcrzburg  W\u00fcrzburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0596-4725","authenticated-orcid":false,"given":"Matthias","family":"Scheiner","sequence":"additional","affiliation":[{"name":"Pharmazeutische und Medizinische Chemie Institut f\u00fcr Pharmazie und Lebensmittelchemie, Julius\u2010Maximilians\u2010Universit\u00e4t W\u00fcrzburg  W\u00fcrzburg 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