CHF5074, a Novel γ-Secretase Modulator, Restores Hippocampal Neurogenesis Potential and Reverses Contextual Memory Deficit in a Transgenic Mouse Model of Alzheimer's Disease
CHF5074, a Novel γ-Secretase Modulator, Restores Hippocampal Neurogenesis Potential and Reverses Contextual Memory Deficit in a Transgenic Mouse Model of Alzheimer's Disease
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DOI：
10.3233/jad-2010-1366
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发表时间：
2010-01-01
影响因子：
4
通讯作者：
Calza, Laura
中科院分区：
文献类型：
--
作者：
Imbimbo, Bruno P.;Giardino, Luciana;Calza, Laura
干扰γ分泌酶（负责从淀粉样β蛋白前体（AβPP）形成淀粉样β（Aβ）肽的酶复合物）的化合物对阿尔茨海默病转基因小鼠模型中斑块沉积的影响是已知的，但关于这些药物对大脑可塑性影响的数据很少。我们评估了长期使用CHF5074（一种新型γ-分泌酶调节剂）治疗对携带AβPP（Tg2576）双重瑞典突变的转基因小鼠的海马神经发生、皮质突触素水平和情境记忆的影响。六个月大的 Tg2576 小鼠接受 CHF5074（饮食中 375 ppm）治疗直至 15 个月大。年龄匹配的对照转基因小鼠和野生型小鼠接受标准饮食。与野生型动物相比，转基因对照显示齿状回中双皮质素阳性神经母细胞的数量、皮质中的突触素强度显着减少，在情境恐惧调节测试中冻结到情境中。与转基因对照相比，CHF5074治疗Tg2576小鼠导致海马神经发生损伤显着减弱（p - 0.036），皮层突触素水平正常化（p < 0.001），皮层斑块负荷减弱（p = 0.033），斑块周围星形胶质细胞反应增加（p = 0.001），并且减弱激活的小胶质细胞（p = 0.040）。这些效应与情境记忆缺陷的完全逆转相关（p = 0.006）。情境记忆与皮质中的突触素免疫反应性显着相关（r = 0.548，p = 0.0038）。
The effects of compounds interfering with gamma-secretase, the enzymatic complex responsible of the formation of the amyloid-beta (A beta) peptide from amyloid-beta protein precursor (A beta PP), on plaque deposition in transgenic mouse models of Alzheimer's disease are known but scanty data are available on the effects of these drugs on brain plasticity. We evaluated the effects of long-term treatment with CHF5074, a new gamma-secretase modulator, on hippocampal neurogenesis, cortical synaptophysin levels, and contextual memory in transgenic mice carrying the double Swedish mutation of A beta PP (Tg2576). Six-month old Tg2576 mice were treated with CHF5074 (375 ppm in the diet) up to 15 months of age. Age-matched control transgenic and wild-type mice received standard diet. Compared to wild-type animals, transgenic controls showed a significant decrease in the number of doublecortin-positive neuroblasts in dentate gyrus, synaptophysin intensity in the cortex, freezing to context in the contextual fear conditioning test. Compared to transgenic controls, CHF5074 treatment of Tg2576 mice resulted in a significant attenuation of the neurogenesis impairment in hippocampus (p - 0.036), normalization of synaptophysin levels in cortex (p < 0.001), attenuation of plaque burden in the cortex (p = 0.033), increases astroglial reaction around plaques (p = 0.001), and attenuation of activated microglia (p = 0.040). These effects were associated to a complete reversal of contextual memory deficit (p = 0.006). Contextual memory significantly correlated with synaptophysin immunoreactivity in the cortex (r = 0.548, p = 0.0038).