Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
J Exp Med. 2018 Mar 5;215(3):927-940. doi: 10.1084/jem.20171831. Epub 2018 Feb 14.
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 (BACE1) mice and bred BACE1 mice with ubiquitin-Cre 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.
BACE1 启动β-淀粉样肽的生成，当异常积累时可能导致阿尔茨海默病（AD）。目前正在开发 BACE1 抑制剂药物来治疗 AD 患者。为了模拟成年人的 BACE1 抑制，我们生成了 BACE1 条件性敲除（BACE1）小鼠，并将 BACE1 小鼠与泛素-Cre 小鼠杂交，以在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）中连续且逐渐增加的 BACE1 缺失能够完全逆转淀粉样蛋白沉积。淀粉样蛋白沉积的这种逆转也导致神经胶质增生和神经突营养不良显著改善。此外，通过长时程增强和情境恐惧条件反射实验确定的突触功能也得到了显著改善，与淀粉样斑块的逆转相关。我们的研究结果表明，在成年期持续和逐渐增加的 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中 BACE1 抑制剂的正确使用提供指导。
