最新成果!逐步抑制BACE1酶活性,可逆转痴呆
2018/02/23
为治疗阿尔兹海默症,科学家们找到了很多目标。其中,β-淀粉样蛋白裂解酶(BACE)就是热门靶点之一。近期,《Journal of Experimental Medicine》一篇文章揭示,逐步抑制BACE1酶,能够完全清除小鼠大脑内淀粉样蛋白病斑的形成,改善动物的认知、记忆能力。


图片来源:网络

这一研究由Cleveland诊所Lerner研究所的科学家们完成,为研发靶向BACE1的抗痴呆药物提供了支撑。


DOI: 10.1084/jem.20171831

β-淀粉样蛋白裂解酶

β-淀粉样蛋白在大脑中的过度累积是阿尔兹海默症典型的病理特征,而BACE1酶是产生这一蛋白的关键酶(分解淀粉样前体蛋白APP)。所以, BACE1酶被认为是阿尔兹海默症治疗药物的热门靶点。

但是,考虑到BACE1参与多种蛋白的分子反应过程(除APP之外),所以科学家们担忧这类药物会产生严重的副作用。早前,默沙东的Verubecestat曾是首个进入临床Ⅲ期的BACE1抑制剂,但是在治疗轻中度老年痴呆试验中并未得到积极的临床结果。

除了治疗之外,BACE1也被认为是预测、诊断阿尔兹海默症发生、发展的重要标志物,目前正处于研究中。

最新研究


The brain of a 10-month-old mouse with Alzheimer's disease (left) is full of amyloid plaques (red) surrounded by activated microglial cells (green). But these hallmarks of Alzheimer's disease are reversed in animals that have gradually lost the BACE1 enzyme (right). Credit: Hu et al., 2018

文章通讯作者Riqiang Yan带领团队发现,完全抑制BACE1会引发小鼠严重的神经发育缺陷。但是,伴随着小鼠衰老,逐步抑制BACE1酶活性,有利于小鼠的健康。

当75天大的成年小鼠开始出现老年痴呆症状(大脑中检测到淀粉样蛋白病斑),它们的后代也会在这个年龄段发生相同的病症,即便它们体内BACE1酶活性比正常水平大约低50%。然而,值得注意的是,当小鼠继续衰老、BACE1活性继续降低时,大脑中的蛋白病斑开始消失,直至完成全没有病斑存在(10个月大)。

抑制BACE1酶活性可以降低β-淀粉样蛋白水平,逆转痴呆的其他病症,例如小胶质细胞的激活、异常的神经衰退。而且,BACE1酶的沉默可以改善痴呆小鼠的学习、记忆能力。

“我们的数据表明,成年小鼠逐步抑制BACE1活性后,能够完全逆转致病蛋白的沉积。这意味着,BACE1抑制剂具有治疗阿尔兹海默症的潜能,且不会产生严重的副作用。” Riqiang Yan强调道。

参考资料:

Researchers successfully reverse Alzheimer's disease in mouse model

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  • BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions

    BACE1 initiates the generation of the β-amyloid peptide, which likely causes Alzheimer’s disease (AD) when accumulated abnormally. BACE1 inhibitory drugs are currently being developed to treat AD patients. To mimic BACE1 inhibition in adults, we generated BACE1 conditional knockout (BACE1fl/fl) mice and bred BACE1fl/fl mice with ubiquitin-CreER mice to induce deletion of BACE1 after passing early developmental stages. Strikingly, sequential and increased deletion of BACE1 in an adult AD mouse model (5xFAD) was capable of completely reversing amyloid deposition. This reversal in amyloid deposition also resulted in significant improvement in gliosis and neuritic dystrophy. Moreover, synaptic functions, as determined by long-term potentiation and contextual fear conditioning experiments, were significantly improved, correlating with the reversal of amyloid plaques. Our results demonstrate that sustained and increasing BACE1 inhibition in adults can reverse amyloid deposition in an AD mouse model, and this observation will help to provide guidance for the proper use of BACE1 inhibitors in human patients.

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