Acute γ-secretase inhibition improves contextual fear conditioning in the Tg2576 mouse model of Alzheimer's disease
Acute γ-secretase inhibition improves contextual fear conditioning in the Tg2576 mouse model of Alzheimer's disease
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DOI：
10.1523/jneurosci.2693-05.2005
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发表时间：
2005-09-28
影响因子：
5.3
通讯作者：
Marquis, KL
中科院分区：
文献类型：
--
作者：
Comery, TA;Martone, RL;Marquis, KL
过度表达人类淀粉样前体蛋白瑞典突变体的转基因小鼠（Tg2576）呈现出与阿尔茨海默病诸多方面相符的生化、病理和行为标志物，包括海马功能受损。在年仅20周的小鼠中就观察到海马依赖的情境恐惧条件反射（CFC）受损。在训练前用磷酸二酯酶 - 4抑制剂咯利普兰（0.1毫克/千克，腹腔注射）治疗后，这种损伤可减轻。在同窝对照小鼠中也观察到与咯利普兰相关的改善，这表明咯利普兰的作用与β - 淀粉样蛋白无关。在训练前（但不是训练后或测试前）用γ - 分泌酶抑制剂（GSI）N - [N -（3,5 - 二氟苯乙酰基） - L - 丙氨酰]S - 苯甘氨酸 - 叔丁酯（DAPT）进行急性治疗，使用能降低脑内β - 淀粉样蛋白浓度的剂量（100毫克/千克），可减轻20至65周龄Tg2576小鼠的损伤。重要的是，DAPT对同窝对照小鼠的行为表现没有影响。这些数据支持β - 淀粉样蛋白在Tg2576小鼠CFC损伤中的作用。此外，它们表明用GSI进行急性治疗可能在阿尔茨海默病中提供改善的认知功能以及疾病修饰作用。
Transgenic mice (Tg2576) overexpressing the Swedish mutation of the human amyloid precursor protein display biochemical, pathological, and behavioral markers consistent with many aspects of Alzheimer's disease, including impaired hippocampal function. Impaired, hippocampal-dependent, contextual fear conditioning (CFC) is observed in mice as young as 20 weeks of age. This impairment can be attenuated after treatment before training with the phosphodiesterase-4 inhibitor rolipram (0.1 mg/kg, i.p.). A rolipram-associated improvement is also observed in the littermate controls, suggesting that the effect of rolipram is independent of beta-amyloid. Acute treatment before training (but not after training or before testing) with the gamma-secretase inhibitor (GSI) N-[ N-(3,5- difluorophenacetyl)-L-alanyl]S-phenylglycine-t- butylester (DAPT), at a dose that reduces brain concentrations of beta-amyloid (100 mg/kg), attenuates the impairment in 20- to 65-week-old Tg2576 mice. Importantly, DAPT had no effect on performance of control littermates. These data are supportive of a role of beta-amyloid in the impairment of CFC in Tg2576 mice. Furthermore, they suggest that acute treatment with GSI may provide improved cognitive functioning as well as disease-modifying effects in Alzheimer's disease.