Caspase-6 Knockout in the 5xFAD Model of Alzheimer's Disease Reveals Favorable Outcome on Memory and Neurological Hallmarks
Caspase-6 Knockout in the 5xFAD Model of Alzheimer's Disease Reveals Favorable Outcome on Memory and Neurological Hallmarks
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DOI：
10.3390/ijms21031144
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发表时间：
2020-02-01
影响因子：
5.6
通讯作者：
Offen, Daniel
中科院分区：
文献类型：
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作者：
Angel, Ariel;Volkman, Rotem;Offen, Daniel
阿尔茨海默病(AD)是一种进行性神经退行性疾病，是老年人最常见的痴呆症。半胱氨酸蛋白酶是半胱氨酸蛋白酶家族，是细胞凋亡和炎症的主要介导者。Caspase-6被认为是AD发病的上游调节因子，因为活性Caspase-6在AD脑内的神经纤维束、神经纤维斑和神经纤维缠结中大量存在。为了进一步阐明caspase-6活性在AD发病机制中的作用，我们将caspase-6基因敲除(C6-KO)小鼠与AD 5xFAD小鼠模型相结合，建立了双转基因小鼠模型。与5xFAD/C6-KO双转基因小鼠相比，5xFAD/C6-KO双转基因小鼠在空间学习、记忆和焦虑/风险评估行为方面的表现有所改善。海马区基因表达分析显示，5xFAD/C6-KO小鼠海马区炎症介质TNF-α水平显著降低，而抗炎细胞因子IL-10水平显著升高。与5xFAD小鼠相比，5xFAD/C6-KO组淀粉样β蛋白斑块显著减少，免疫组织化学分析显示激活的小胶质细胞和星形胶质细胞水平降低。综上所述，这些结果表明caspase-6在5xFAD AD模型的病理中发挥了重要作用，并提示caspase-6作为AD的潜在治疗靶点的进一步验证。
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia in the elderly. Caspases, a family of cysteine proteases, are major mediators of apoptosis and inflammation. Caspase-6 is considered to be an up-stream modulator of AD pathogenesis as active caspase-6 is abundant in neuropil threads, neuritic plaques, and neurofibrillary tangles of AD brains. In order to further elucidate the role of caspase-6 activity in the pathogenesis of AD, we produced a double transgenic mouse model, combining the 5xFAD mouse model of AD with caspase-6 knock out (C6-KO) mice. Behavioral examinations of 5xFAD/C6-KO double transgenic mice showed improved performance in spatial learning, memory, and anxiety/risk assessment behavior, as compared to 5xFAD mice. Hippocampal mRNA expression analyses showed significantly reduced levels of inflammatory mediator TNF-alpha, while the anti-inflammatory cytokine IL-10 was increased in 5xFAD/C6-KO mice. A significant reduction in amyloid-beta plaques could be observed and immunohistochemistry analyses showed reduced levels of activated microglia and astrocytes in 5xFAD/C6-KO, compared to 5xFAD mice. Together, these results indicate a substantial role for caspase-6 in the pathology of the 5xFAD model of AD and suggest further validation of caspase-6 as a potential therapeutic target for AD.