Abstract：
Neuronal loss is the central issue in Alzheimer\'s disease (AD), yet no treatment developed so far can halt AD-associated neurodegeneration. Here, we developed a monoclonal antibody (mAb2A7) against 217 site-phosphorylated human tau (p-tau217) and observed that p-tau217 levels positively correlated with brain atrophy and cognitive impairment in AD patients. Intranasal administration efficiently delivered mAb2A7 into male PS19 tauopathic mouse brain with target engagement and reduced tau pathology/aggregation with little effect on total soluble tau. Further, mAb2A7 treatment blocked apoptosis-associated neuronal loss and brain atrophy, reversed cognitive deficits, and improved motor function in male tauopathic mice. Proteomic analysis revealed that mAb2A7 treatment reversed alterations mainly in proteins associated with synaptic functions observed in murine tauopathy and AD brain. An antibody (13G4) targeting total tau also attenuated tau-associated pathology and neurodegeneration but impaired the motor function of male tauopathic mice. These results implicate p-tau217 as a potential therapeutic target for AD-associated neurodegeneration.
摘要：
神经元丢失是阿尔茨海默病（AD）的中心问题，然而，迄今为止尚未开发出可以阻止AD相关神经变性的治疗方法。这里,我们开发了针对217位点磷酸化的人tau(p-tau217)的单克隆抗体(mAb2A7),并观察到p-tau217水平与AD患者的脑萎缩和认知障碍呈正相关.鼻内给药有效地将mAb2A7递送到雄性PS19tau病鼠脑中,具有靶接合和减少tau病理/聚集,而对总可溶性tau几乎没有影响。Further,mAb2A7治疗阻断了凋亡相关的神经元丢失和脑萎缩，逆转的认知缺陷，并改善雄性牛磺酸病鼠的运动功能。蛋白质组学分析显示，mAb2A7治疗逆转了主要与鼠tau蛋白病和AD脑中观察到的突触功能相关的蛋白质的改变。靶向总tau的抗体(13G4)也减弱了tau相关的病理学和神经变性,但损害了雄性tau病鼠的运动功能。这些结果暗示p-tau217是AD相关神经变性的潜在治疗靶标。
