BACE1 is the rate-limiting protease in the production of synaptotoxic β-amyloid (Aβ) species and hence one of the prime drug targets for potential therapy of Alzheimer’s disease (AD). However, so far pharmacological BACE1 inhibition failed to rescue the cognitive decline in mild-to-moderate AD patients, which indicates that treatment at the symptomatic stage might be too late. In the current study, chronic in vivo two-photon microscopy was performed in a transgenic AD model to monitor the impact of pharmacological BACE1 inhibition on early β-amyloid pathology. The longitudinal approach allowed to assess the kinetics of individual plaques and associated presynaptic pathology, before and throughout treatment. BACE1 inhibition could not halt but slow down progressive β-amyloid deposition and associated synaptic pathology. Notably, the data revealed that the initial process of plaque formation, rather than the subsequent phase of gradual plaque growth, is most sensitive to BACE1 inhibition. This finding of particular susceptibility of plaque formation has profound implications to achieve optimal therapeutic efficacy for the prospective treatment of AD.

BACE1 是产生突触毒性 β-淀粉样蛋白 (Aβ) 的限速蛋白酶，因此是阿尔茨海默病 (AD) 潜在治疗的主要药物靶标之一。然而，迄今为止，药物BACE1抑制未能挽救轻至中度AD患者的认知能力下降，这表明在症状阶段进行治疗可能为时已晚。在目前的研究中，在转基因 AD 模型中进行了慢性体内双光子显微镜检查，以监测药理学 BACE1 抑制对早期 β-淀粉样蛋白病理学的影响。纵向方法可以在治疗之前和整个治疗过程中评估单个斑块的动力学和相关的突触前病理。BACE1 抑制不能阻止但减缓进行性 β-淀粉样蛋白沉积和相关的突触病理。值得注意的是，数据显示，斑块形成的初始过程，而不是斑块逐渐生长的后续阶段，对 BACE1 抑制最敏感。斑块形成特别易感性的这一发现对于实现 AD 前瞻性治疗的最佳治疗效果具有深远的意义。