The BACE1-Specific DNA Aptamer A1 Rescues Amyloid-β Pathology and Behavioral Deficits in a Mouse Model of Alzheimer's Disease
The BACE1-Specific DNA Aptamer A1 Rescues Amyloid-β Pathology and Behavioral Deficits in a Mouse Model of Alzheimer's Disease
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BACE1 特异性 DNA 适体 A1 拯救阿尔茨海默氏病小鼠模型中的淀粉样蛋白-β 病理学和行为缺陷
DOI：
10.1089/nat.2019.0812
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发表时间：
2019-09-12
影响因子：
4
通讯作者：
Zhang, Xing-Mei
中科院分区：
文献类型：
--
作者：
Liang, Zhi-Man;Peng, Yong-Hua;Zhang, Xing-Mei
大脑中的β淀粉样蛋白（A β）斑块沉积被认为是阿尔茨海默病（AD）的主要病理标志物之一。淀粉样前体蛋白（APP）通过β-淀粉样蛋白酶β位点APP裂解酶1（BACE 1）和γ-分泌酶的连续蛋白水解裂解产生A β。因此，BACE 1抑制是治疗AD的一个非常有吸引力的靶点。我们之前的工作发现了一种名为A1的DNA适体，它可以以高亲和力和特异性与BACE 1结合，并在AD细胞模型中对BACE 1活性表现出明显的抑制作用。本研究的目的是测试适配体A1在Tg 6799小鼠中的作用。将4月龄Tg 6799小鼠随机分为两组，分别通过脑室内注射适体A1和无效适体A1 scr。随后的行为实验表明，用适体A1治疗改善了AD小鼠的认知能力。Western blot结果显示，BACE 1和可溶性淀粉样前体蛋白β（sAPP β）的表达在A1处理的小鼠中显著降低。此外，适体A1降低了AD小鼠中A β（42）的含量以及老年斑的数量和密度。因此，我们的研究结果表明，适配体A1是一种新的特异性和有效的BACE 1抑制剂，是一个有前途的潜在目标，用于治疗AD。
Amyloid-beta (A beta) plaque deposits in the brain are considered to be one of the main pathological markers of Alzheimer's disease (AD). The sequential proteolytic cleavage of amyloid precursor protein (APP) by the aspartyl proteases beta-site APP-cleaving enzyme 1 (BACE1) and gamma-secretase produces A beta. Therefore, BACE1 inhibition is a very attractive target for the treatment of AD. Our previous work identified a DNA aptamer named A1 that can bind to BACE1 with high affinity and specificity and exhibits a distinct inhibitory effect on BACE1 activity in an AD cell model. The purpose of this research was to test the effect of aptamer A1 in Tg6799 mice. Four-month-old Tg6799 mice were randomly divided into two groups and treated with aptamer A1 and ineffective aptamer A1scr, respectively, by intracerebroventricular injection. Subsequent behavioral experiments showed that treatment with the aptamer A1 improved the cognitive abilities of the AD mice. Western blot indicated that BACE1 and soluble amyloid precursor protein beta (sAPP beta) expression significantly decreased in the A1-treated mice. Moreover, aptamer A1 reduced the content of A beta(42) and the number and density of senile plaques in AD mice. Therefore, our results indicate that aptamer A1 is a novel specific and potent BACE1 inhibitor and is a promising potential target for the treatment of AD.