Alzheimer's disease pathology is attenuated in a CD38-deficient mouse model.
Alzheimer's disease pathology is attenuated in a CD38-deficient mouse model.
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DOI：
10.1002/ana.24425
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发表时间：
2015-07
影响因子：
11.2
通讯作者：
Levy A
中科院分区：
文献类型：
--
作者：
Blacher E;Dadali T;Bespalko A;Haupenthal VJ;Grimm MO;Hartmann T;Lund FE;Stein R;Levy A
阿尔茨海默病（AD）相关的痴呆是由于脑内淀粉样蛋白β（Aβ）沉积和伴随的神经炎症引起的组织损伤。由神经元、星形胶质细胞和小胶质细胞表达的NAD糖水解酶CD 38通过降解NAD和抑制其他NAD消耗酶的活性以及通过产生调节钙信号传导和炎性细胞迁移的NAD衍生代谢物来调节脑和其他组织中的炎症和修复过程。鉴于CD 38在神经炎症和修复中的作用，我们研究了CD 38缺失对AD病理学的影响。我们将APPswePS 1 ΔE9（APP.PS）小鼠与Cd 38 −/−小鼠杂交，以产生AD易感性CD 38缺陷动物（APP.PS.Cd38−/−），并检查两组中的AD相关表型。与APP.PS小鼠相比，APP. PS. Cd 38 −/−小鼠的Aβ斑块负荷和可溶性Aβ水平显著降低，这与空间学习能力的改善相关。尽管CD 38缺陷导致小胶质细胞/巨噬细胞（MM）蓄积减少，但CD 38 −/−和CD 38 +/+ MM的转录谱相似，表明APP. PS. CD 38 −/−小鼠中Aβ负荷减少并非由于MM活化/功能改变所致。相反，APP. PS. Cd 38 −/−神经元培养物分泌较少的Aβ，当APP.PS神经元培养物用阻断CD 38酶活性或CD 38衍生代谢物控制的信号通路的抑制剂处理时，这种减少被模拟。此外，APP.PS.Cd38−/−小鼠的β和γ-分泌酶活性降低，这与Aβ产生减少相关。在AD的APP.PS模型中，CD 38调节AD病理，提示CD 38可能是AD治疗的新靶点。
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 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. 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. 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. CD38 regulates AD pathology in the APP.PS model of AD, suggesting that CD38 may be a novel target for AD treatment.
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影响因子：
4.2
作者：
Gong B;Pan Y;Vempati P;Zhao W;Knable L;Ho L;Wang J;Sastre M;Ono K;Sauve AA;Pasinetti GM
通讯作者：
Pasinetti GM
影响因子：
5.6
作者：
Grimm MO;Haupenthal VJ;Rothhaar TL;Zimmer VC;Grösgen S;Hundsdörfer B;Lehmann J;Grimm HS;Hartmann T
通讯作者：
Hartmann T
DOI：
10.1016/j.bbrc.2006.05.042
发表时间：
2006-07-14
影响因子：
3.1
作者：
Aksoy, Pinar;White, Thomas A.;Chini, Eduardo N.
通讯作者：
Chini, Eduardo N.
影响因子：
2.9
作者：
MIZUGUCHI, M;OTSUKA, N;IKEDA, K
通讯作者：
IKEDA, K
影响因子：
13.9
作者：
O'Brien RJ;Wong PC
通讯作者：
Wong PC