BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions
BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions
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DOI：
10.1084/jem.20171831
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发表时间：
2018-03-01
影响因子：
15.3
通讯作者：
Yan, Riqiang
中科院分区：
文献类型：
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作者：
Hu, Xiangyou;Das, Brati;Yan, Riqiang
BACE1启动β -淀粉样肽的产生，当其异常积累时可能导致阿尔茨海默病（AD）。目前正在开发BACE1抑制药物来治疗AD患者。为了模拟BACE1在成人中的抑制作用，我们培育了BACE1条件敲除（BACE1(fl/fl)）小鼠，并将BACE1（fl/fl）小鼠与泛素- cre （ER）小鼠杂交，在经过早期发育阶段后诱导BACE1的缺失。引人注目的是，在成年AD小鼠模型（5xFAD）中，连续和增加的BACE1缺失能够完全逆转淀粉样蛋白沉积。淀粉样蛋白沉积的逆转也导致胶质瘤和神经性营养不良的显著改善。此外，通过长期增强和情境恐惧条件反射实验确定的突触功能显著改善，与淀粉样斑块的逆转相关。我们的研究结果表明，在成人中持续和增加BACE1抑制可以逆转AD小鼠模型中的淀粉样蛋白沉积，这一观察结果将有助于为人类患者正确使用BACE1抑制剂提供指导。
BACE1 initiates the generation of the beta-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 (BACE1(fl/fl)) mice and bred BACE1(fl/fl) mice with ubiquitin-Cre(ER) 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.