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The nicotinamide adenine dinucleotide (NAD) glycohydrolase CD38, which is expressed by neurons, astrocytes, and microglial cells, regulates inflammatory and repair processes in the brain and other tissues by degrading NAD and repressing the activity of other NAD\u2010consuming enzymes and by producing NAD\u2010derived metabolites that regulate calcium signaling and migration of inflammatory cells. Given the role of CD38 in neuroinflammation and repair, we examined the effect of CD38 deletion on AD pathology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We crossed APPswePS1\u0394E9 (APP.PS) mice with <jats:italic>Cd38<jats:sup>\u2212<\/jats:sup><jats:sup>\/<\/jats:sup><jats:sup>\u2212<\/jats:sup><\/jats:italic> mice to generate AD\u2010prone CD38\u2010deficient animals (APP.PS.<jats:italic>Cd38<jats:sup>\u2212<\/jats:sup><jats:sup>\/<\/jats:sup><jats:sup>\u2212<\/jats:sup><\/jats:italic>) and examined AD\u2010related phenotypes in both groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>APP.PS.<jats:italic>Cd38<jats:sup>\u2212<\/jats:sup><jats:sup>\/<\/jats:sup><jats:sup>\u2212<\/jats:sup><\/jats:italic> mice exhibited significant reductions in A\u03b2 plaque load and soluble A\u03b2 levels compared to APP.PS mice, and this correlated with improved spatial learning. Although CD38 deficiency resulted in decreased microglia\/macrophage (MM) accumulation, the transcription profile of the <jats:italic>Cd38<jats:sup>\u2212<\/jats:sup><jats:sup>\/<\/jats:sup><jats:sup>\u2212<\/jats:sup><\/jats:italic> and <jats:italic>Cd38<jats:sup>+\/<\/jats:sup><jats:sup>+<\/jats:sup><\/jats:italic> MM was similar, suggesting that the decreased A\u03b2 burden in APP.PS.<jats:italic>Cd38<jats:sup>\u2212<\/jats:sup><jats:sup>\/<\/jats:sup><jats:sup>\u2212<\/jats:sup><\/jats:italic> mice was not due to alterations in MM activation\/function. Instead, APP.PS.<jats:italic>Cd38<jats:sup>\u2212<\/jats:sup><jats:sup>\/<\/jats:sup><jats:sup>\u2212<\/jats:sup><\/jats:italic> neuronal cultures secreted less A\u03b2 and this reduction was mimicked when APP.PS neuronal cultures were treated with inhibitors that blocked CD38 enzyme activity or the signaling pathways controlled by CD38\u2010derived metabolites. Furthermore, \u03b2\u2010 and \u03b3\u2010secretase activity was decreased in APP.PS.<jats:italic>Cd38<jats:sup>\u2212<\/jats:sup><jats:sup>\/<\/jats:sup><jats:sup>\u2212<\/jats:sup><\/jats:italic> mice, which correlated with decreased A\u03b2 production.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>CD38 regulates AD pathology in the APP.PS model of AD, suggesting that CD38 may be a novel target for AD treatment. Ann Neurol 2015;78:88\u2013103<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.24425","type":"journal-article","created":{"date-parts":[[2015,4,20]],"date-time":"2015-04-20T11:19:16Z","timestamp":1429528756000},"page":"88-103","source":"Crossref","is-referenced-by-count":120,"title":["Alzheimer's disease pathology is attenuated in a <scp>CD<\/scp>38\u2010deficient mouse model"],"prefix":"10.1002","volume":"78","author":[{"given":"Eran","family":"Blacher","sequence":"first","affiliation":[{"name":"Department of Neurobiology George S. Wise Faculty of Life Sciences, Tel Aviv University Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tulin","family":"Dadali","sequence":"additional","affiliation":[{"name":"Department of Microbiology University of Alabama at Birmingham Birmingham AL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Bespalko","sequence":"additional","affiliation":[{"name":"Department of Neurobiology George S. Wise Faculty of Life Sciences, Tel Aviv University Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viola J.","family":"Haupenthal","sequence":"additional","affiliation":[{"name":"German Institute for Dementia Prevention Saarland University  Homburg Germany"},{"name":"Neurodegeneration and Neurobiology Saarland University  Homburg Germany"},{"name":"Experimental Neurology Saarland University  Homburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus O. W.","family":"Grimm","sequence":"additional","affiliation":[{"name":"German Institute for Dementia Prevention Saarland University  Homburg Germany"},{"name":"Neurodegeneration and Neurobiology Saarland University  Homburg Germany"},{"name":"Experimental Neurology Saarland University  Homburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Hartmann","sequence":"additional","affiliation":[{"name":"German Institute for Dementia Prevention Saarland University  Homburg Germany"},{"name":"Neurodegeneration and Neurobiology Saarland University  Homburg Germany"},{"name":"Experimental Neurology Saarland University  Homburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances E.","family":"Lund","sequence":"additional","affiliation":[{"name":"Department of Microbiology University of Alabama at Birmingham Birmingham AL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reuven","family":"Stein","sequence":"additional","affiliation":[{"name":"Department of Neurobiology George S. 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