Chu Fangxuan, Tan Ruxin, Wang Xin, Zhou Xiaoqing, Ma Ren, Ma Xiaoxu, Li Ying, Liu Ruixu, Zhang Chunlan, Liu Xu, Yin Tao, Liu Zhipeng
Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China.
Tianjin Institutes of Health Science, Tianjin, 301600, China.
Research (Wash D C). 2023 May 8;6:0130. doi: 10.34133/research.0130. eCollection 2023.
The neuropathological features of Alzheimer's disease include amyloid plaques. Rapidly emerging evidence suggests that Piezo1, a mechanosensitive cation channel, plays a critical role in transforming ultrasound-related mechanical stimuli through its trimeric propeller-like structure, but the importance of Piezo1-mediated mechanotransduction in brain functions is less appreciated. However, apart from mechanical stimulation, Piezo1 channels are strongly modulated by voltage. We assume that Piezo1 may play a role in converting mechanical and electrical signals, which could induce the phagocytosis and degradation of Aβ, and the combined effect of mechanical and electrical stimulation is superior to single mechanical stimulation. Hence, we design a transcranial magneto-acoustic stimulation (TMAS) system, based on transcranial ultrasound stimulation (TUS) within a magnetic field that combines a magneto-acoustic coupling effect electric field and the mechanical force of ultrasound, and applied it to test the above hypothesis in 5xFAD mice. Behavioral tests, in vivo electrophysiological recordings, Golgi-Cox staining, enzyme-linked immunosorbent assay, immunofluorescence, immunohistochemistry, real-time quantitative PCR, Western blotting, RNA sequencing, and cerebral blood flow monitoring were used to assess whether TMAS can alleviate the symptoms of AD mouse model by activating Piezo1. TMAS treatment enhanced autophagy to promote the phagocytosis and degradation of β-amyloid through the activation of microglial Piezo1 and alleviated neuroinflammation, synaptic plasticity impairment, and neural oscillation abnormalities in 5xFAD mice, showing a stronger effect than ultrasound. However, inhibition of Piezo1 with an antagonist, GsMTx-4, prevented these beneficial effects of TMAS. This research indicates that Piezo1 can transform TMAS-related mechanical and electrical stimuli into biochemical signals and identifies that the favorable effects of TMAS on synaptic plasticity in 5xFAD mice are mediated by Piezo1.
阿尔茨海默病的神经病理学特征包括淀粉样斑块。迅速出现的证据表明，机械敏感阳离子通道Piezo1通过其三聚体螺旋桨样结构在转化超声相关机械刺激中起关键作用，但Piezo1介导的机械转导在脑功能中的重要性尚未得到充分认识。然而，除了机械刺激外，Piezo1通道还受到电压的强烈调节。我们假设Piezo1可能在转换机械和电信号中发挥作用，这可能诱导Aβ的吞噬和降解，并且机械和电刺激的联合作用优于单一机械刺激。因此，我们基于磁场内的经颅超声刺激（TUS）设计了一种经颅磁声刺激（TMAS）系统，该系统结合了磁声耦合效应电场和超声的机械力，并将其应用于5xFAD小鼠以检验上述假设。行为测试、体内电生理记录、高尔基-考克斯染色、酶联免疫吸附测定、免疫荧光、免疫组织化学、实时定量PCR、蛋白质印迹、RNA测序和脑血流监测被用于评估TMAS是否可以通过激活Piezo1来减轻AD小鼠模型的症状。TMAS治疗通过激活小胶质细胞Piezo1增强自噬，促进β淀粉样蛋白的吞噬和降解，并减轻5xFAD小鼠的神经炎症、突触可塑性损伤和神经振荡异常，显示出比超声更强的效果。然而，用拮抗剂GsMTx-4抑制Piezo1可阻止TMAS的这些有益作用。这项研究表明，Piezo1可以将TMAS相关的机械和电刺激转化为生化信号，并确定TMAS对5xFAD小鼠突触可塑性的有利作用是由Piezo1介导的。
