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^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.

BACE1启动β-淀粉样肽的生成，当异常积累时，它可能引起阿尔茨海默氏病（AD）。目前正在开发BACE1抑制药物来治疗AD患者。为了模拟成年人中的BACE1抑制作用，我们生成了BACE1条件性基因敲除（BACE1 ^{fl / fl}）小鼠，并用泛素-Cre ^ER繁殖了BACE1 ^{fl / fl}小鼠小鼠在经过早期发育阶段后诱导BACE1缺失。令人惊讶的是，在成年AD小鼠模型（5xFAD）中，BACE1的连续和增加的缺失能够完全逆转淀粉样蛋白的沉积。淀粉样蛋白沉积的这种逆转还导致神经胶质增生和神经营养不良症的显着改善。此外，通过长期增强和情境恐惧调节实验确定的突触功能得到了显着改善，与淀粉样斑块的逆转有关。我们的结果表明，成年人中持续不断增加的BACE1抑制作用可以逆转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在人类患者中正确使用BACE1抑制剂提供指导。