Voluntary Exercise Promotes Glymphatic Clearance of Amyloid Beta and Reduces the Activation of Astrocytes and Microglia in Aged Mice.
Voluntary Exercise Promotes Glymphatic Clearance of Amyloid Beta and Reduces the Activation of Astrocytes and Microglia in Aged Mice.
复制标题
自愿运动促进老年小鼠类淀粉样蛋白的类淋巴清除并减少星形胶质细胞和小胶质细胞的活化
DOI：
10.3389/fnmol.2017.00144
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发表时间：
2017
影响因子：
4.8
通讯作者：
Lan Y
中科院分区：
文献类型：
--
作者：
He XF;Liu DX;Zhang Q;Liang FY;Dai GY;Zeng JS;Pei Z;Xu GQ;Lan Y
衰老的特征是慢性炎症，导致突触功能障碍和痴呆，因为蛋白质废物的清除减少。蛋白质的清除部分取决于血脑屏障（BBB）的渗透或脑脊液（CSF）和间质液（ISF）之间的水和可溶性内容物的交换。大量证据表明，体育锻炼可以改善老年性神经退行性疾病（如阿尔茨海默病（AD））的记忆和认知，但体育锻炼对胶质淋巴清除，BBB通透性和神经炎症的影响尚不清楚。在这项研究中，胶质淋巴清除和血脑屏障通透性进行了评估，在老年小鼠体内使用双光子成像。采用免疫荧光法和酶联免疫吸附试验（ELISA）检测星形胶质细胞水通道蛋白4（AQP 4）的表达、星形胶质细胞和小胶质细胞的活化以及β淀粉样蛋白（Aβ）的积累;用Thy 1-绿色荧光蛋白（GFP）转基因小鼠和免疫荧光染色研究突触功能。自由轮跑能显著改善老年小鼠水迷宫认知功能，加快胶质淋巴清除效率，但对血脑屏障通透性无影响。星形胶质细胞和小胶质细胞数量减少，AQP 4表达增加，星形胶质细胞AQP 4分布重排。Aβ积聚减少，而树突、树突棘和突触后密度蛋白（PSD 95）增加。我们的研究表明，自愿轮运行加速胶质淋巴清除，但不是血脑屏障渗透，改善星形胶质细胞AQP 4的表达和极化，衰减淀粉样斑块和神经炎症的积累，并最终保护小鼠免受突触功能障碍和空间认知能力下降。这些数据表明，运动诱导的神经保护在老化的大脑可能的机制。
Age is characterized by chronic inflammation, leading to synaptic dysfunction and dementia because the clearance of protein waste is reduced. The clearance of proteins depends partly on the permeation of the blood–brain barrier (BBB) or on the exchange of water and soluble contents between the cerebrospinal fluid (CSF) and the interstitial fluid (ISF). A wealth of evidence indicates that physical exercise improves memory and cognition in neurodegenerative diseases during aging, such as Alzheimer’s disease (AD), but the influence of physical training on glymphatic clearance, BBB permeability and neuroinflammation remains unclear. In this study, glymphatic clearance and BBB permeability were evaluated in aged mice using in vivo two-photon imaging. The mice performed voluntary wheel running exercise and their water-maze cognition was assessed; the expression of the astrocytic water channel aquaporin 4 (AQP4), astrocyte and microglial activation, and the accumulation of amyloid beta (Aβ) were evaluated with immunofluorescence or an enzyme-linked immunosorbent assay (ELISA); synaptic function was investigated with Thy1–green fluorescent protein (GFP) transgenic mice and immunofluorescent staining. Voluntary wheel running significantly improved water-maze cognition in the aged mice, accelerated the efficiency of glymphatic clearance, but which did not affect BBB permeability. The numbers of activated astrocytes and microglia decreased, AQP4 expression increased, and the distribution of astrocytic AQP4 was rearranged. Aβ accumulation decreased, whereas dendrites, dendritic spines and postsynaptic density protein (PSD95) increased. Our study suggests that voluntary wheel running accelerated glymphatic clearance but not BBB permeation, improved astrocytic AQP4 expression and polarization, attenuated the accumulation of amyloid plaques and neuroinflammation, and ultimately protected mice against synaptic dysfunction and a decline in spatial cognition. These data suggest possible mechanisms for exercise-induced neuroprotection in the aging brain.