Leptin reduces pathology and improves memory in a transgenic mouse model of Alzheimer's disease.
Leptin reduces pathology and improves memory in a transgenic mouse model of Alzheimer's disease.
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DOI：
10.3233/jad-2010-1308
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Casadesus G
中科院分区：
文献类型：
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作者：
Greco SJ;Bryan KJ;Sarkar S;Zhu X;Smith MA;Ashford JW;Johnston JM;Tezapsidis N;Casadesus G
我们以前在体外和体内模型中报道过瘦素的抗淀粉样蛋白生成作用，最近，我们证明了瘦素在神经元细胞中减少tau磷酸化的能力。本研究检测了瘦素在6个月大的CRND8转基因小鼠（TgCRND8）治疗8周后改善阿尔茨海默病（AD）样病理的功效。经leptin处理的转基因小鼠，其脑提取物（降低52%，p=0.047）和血清（降低55%，p=0.049）中淀粉样蛋白-β (Aβ)1-40水平均显著降低（ELISA检测），免疫细胞化学检测海马中淀粉样蛋白负荷显著降低（降低47%，p=0.041）。大脑中a β水平的降低与淀粉样蛋白-β前体C99 c末端片段水平的降低相关，这与β分泌酶在调节瘦素作用中的作用一致。此外，通过AT8和抗tau- ser396抗体检测，瘦素处理的TgCRND8小鼠的磷酸化tau水平显著降低。重要的是，在治疗4周或8周后，与盐水处理的对照组相比，瘦素处理的TgCRND8动物血浆中的c反应蛋白、肿瘤坏死因子-α和皮质醇水平没有显著升高，表明没有炎症反应。这些生化和病理变化与行为改善相关，早在治疗4周后，就有新的物体识别测试记录，特别是治疗8周后的情境和暗示恐惧条件反射测试。在这些行为测试中，瘦素处理的TgCRND8动物明显优于盐水处理的幼崽。这些发现有力地证明了瘦素在阿尔茨海默病转基因动物中作为一种疾病修饰治疗药物的潜力，使人们对其在人类中的安全性和有效性感到乐观。
We have previously reported anti-amyloidogenic effects of leptin using in vitro and in vivo models and, more recently, demonstrated the ability of leptin to reduce tau phosphorylation in neuronal cells. The present study examined the efficacy of leptin in ameliorating the Alzheimer’s disease (AD)-like pathology in 6-month old CRND8 transgenic mice (TgCRND8) following 8 weeks of treatment. Leptin-treated transgenic mice showed significantly reduced levels of amyloid-β (Aβ)1-40 in both brain extracts (52% reduction, p=0.047) and serum (55% reduction, p=0.049), as detected by ELISA, and significant reduction in amyloid burden (47% reduction, p=0.041) in the hippocampus, as detected by immunocytochemistry. The decrease in the levels of Aβ in the brain correlated with a decrease in the levels of C99 C-terminal fragments of the amyloid-β protein precursor, consistent with a role for β-secretase in mediating the effect of leptin. In addition, leptin-treated TgCRND8 mice had significantly lower levels of phosphorylated tau, as detected by AT8 and anti-tau-Ser396 antibodies. Importantly, after 4 or 8 weeks of treatment, there was no significant increase in the levels of C-reactive protein, tumor necrosis factor-α, and cortisol in the plasma of leptin-treated TgCRND8 animals compared to saline-treated controls, indicating no inflammatory reaction. These biochemical and pathological changes were correlated with behavioral improvements, as early as after 4 weeks of treatment, as recorded by a novel object recognition test and particularly the contextual and cued fear conditioning test after 8 weeks of treatment. Leptin-treated TgCRND8 animals significantly outperformed saline-treated littermates in these behavioral tests. These findings solidly demonstrate the potential for leptin as a disease modifying therapeutic in transgenic animals of AD, driving optimism for its safety and efficacy in humans.