title: Alzheimer's disease pathology is attenuated in a CD38-deficient mouse model.
abstract: OBJECTIVE
  Alzheimer's disease (AD)-associated dementia is due to tissue damage caused by amyloid β (Aβ) deposition within the brain and by accompanying neuroinflammation. 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-consuming enzymes and by producing NAD-derived 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.
  
  
  METHODS
  We crossed APPswePS1ΔE9 (APP.PS) mice with Cd38(-) (/) (-) mice to generate AD-prone CD38-deficient animals (APP.PS.Cd38(-) (/) (-) ) and examined AD-related phenotypes in both groups.
  
  
  RESULTS
  APP.PS.Cd38(-) (/) (-) mice exhibited significant reductions in Aβ plaque load and soluble Aβ 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 Cd38(-) (/) (-) and Cd38(+/) (+) MM was similar, suggesting that the decreased Aβ burden in APP.PS.Cd38(-) (/) (-) mice was not due to alterations in MM activation/function. Instead, APP.PS.Cd38(-) (/) (-) neuronal cultures secreted less Aβ 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-derived metabolites. Furthermore, β- and γ-secretase activity was decreased in APP.PS.Cd38(-) (/) (-) mice, which correlated with decreased Aβ production.
  
  
  CONCLUSIONS
  CD38 regulates AD pathology in the APP.PS model of AD, suggesting that CD38 may be a novel target for AD treatment.
authors.affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Blacher
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Tulin
authors.initials: T
authors.lastname: Dadali
authors.affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Alina
authors.initials: A
authors.lastname: Bespalko
authors.affiliation: German Institute for Dementia Prevention, Saarland University, Homburg, Germany.|Neurodegeneration and Neurobiology, Saarland University, Homburg, Germany.|Experimental Neurology, Saarland University, Homburg, Germany.
authors.forename: Viola J
authors.initials: VJ
authors.lastname: Haupenthal
authors.affiliation: German Institute for Dementia Prevention, Saarland University, Homburg, Germany.|Neurodegeneration and Neurobiology, Saarland University, Homburg, Germany.|Experimental Neurology, Saarland University, Homburg, Germany.
authors.forename: Marcus O W
authors.initials: MO
authors.lastname: Grimm
authors.affiliation: German Institute for Dementia Prevention, Saarland University, Homburg, Germany.|Neurodegeneration and Neurobiology, Saarland University, Homburg, Germany.|Experimental Neurology, Saarland University, Homburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Hartmann
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Frances E
authors.initials: FE
authors.lastname: Lund
authors.affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.|Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Reuven
authors.initials: R
authors.lastname: Stein
authors.affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.|Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Levy
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D002478:Cells, Cultured; D004195:Disease Models, Animal; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism*; D065853:Spatial Learning; D059467:Transcriptome
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1; D053829:Amyloid Precursor Protein Secretases