Abstract：
Amyloid beta (Aβ) peptides, which aggregate to form neocortical plaques in Alzheimer\'s disease, exist in states that range from soluble monomers and oligomers/protofibrils to insoluble fibrillar amyloid. The present study evaluated the effects of mAb158, a mouse monoclonal antibody version of lecanemab that preferentially binds to soluble Aβ protofibrils, in aged transgenic mice (Tg2576) with Aβ pathology. Female Tg2576 mice (12 months old) received weekly intraperitoneal mAb158 (35 mg/kg) or vehicle for 4 weeks or for 18 weeks, with or without a subsequent 12-week off-treatment period. Aβ protofibril levels were significantly lower in mAb158-treated animals at both 4 and 18 weeks, while longer treatment duration (18 weeks) was required to observe significantly lower Aβ42 levels in insoluble brain fractions and lower Aβ plaque load. Following the off-treatment period, comparison of the vehicle- and mAb158-treated mice demonstrated that the Aβ protofibril levels, insoluble Aβ42 levels and Aβ plaque load remained significantly lower in mAb158-treated animals, as compared with age-matched controls. However, there was a significant increase of brain accumulation of both the Aβ protofibril levels, insoluble Aβ42 levels and Aβ plaque load after treatment cessation. Thus, repeated mAb158 treatment of aged Tg2576 mice first reduced Aβ protofibril levels within 4 weeks of treatment, which then was followed by a reduction of amyloid plaque pathology within 18 weeks of treatment. These effects were maintained 12 weeks after the final dose, indicating that mAb158 had a disease-modifying effect on the Aβ pathology in this mouse model. In addition, brain accumulation of both Aβ protofibril levels and amyloid pathology progressed after discontinuation of the treatment which supports the importance of continued treatment with mAb158 to maintain the effects on Aβ pathology.
摘要：
淀粉样β（Aβ）肽，在阿尔茨海默病中聚集形成新皮质斑块，存在于从可溶性单体和低聚物/原纤维到不溶性纤维状淀粉样蛋白的状态。本研究评估了mAb158的作用，mAb158是一种小鼠单克隆抗体，可优先与可溶性Aβ原纤维结合，在具有Aβ病理的老年转基因小鼠(Tg2576)中。雌性Tg2576小鼠（12月龄）每周接受腹膜内mAb158（35mg/kg）或媒介物4周或18周，有或没有随后的12周的非治疗期。Aβ原原纤维水平在mAb158处理的动物中在4周和18周时显著降低,而需要更长的治疗时间（18周）才能观察到不溶性脑部分中Aβ42水平的显着降低和Aβ斑块负荷的降低。在非治疗期之后，赋形剂和mAb158处理的小鼠的比较表明，Aβ原原纤维水平，在mAb158处理的动物中，不溶性Aβ42水平和Aβ斑块负荷仍然显着降低，与年龄匹配的对照组相比。然而,两个Aβ原原纤维水平的大脑积累都显着增加，治疗停止后不溶性Aβ42水平和Aβ斑块负荷。因此，重复mAb158治疗老年Tg2576小鼠首先在治疗4周内降低Aβ原原纤维水平，然后在治疗的18周内减少淀粉样蛋白病理，这些效果在最终剂量后维持12周，表明mAb158对该小鼠模型中的Aβ病理具有疾病改善作用。此外,停止治疗后，Aβ原原纤维水平和淀粉样蛋白病理的大脑积累均有进展，这支持了继续用mAb158治疗以维持对Aβ病理的影响的重要性。
