Mechanical injuries of neurons induce tau mislocalization to dendritic spines and tau-dependent synaptic dysfunction
Mechanical injuries of neurons induce tau mislocalization to dendritic spines and tau-dependent synaptic dysfunction
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DOI：
10.1073/pnas.2008306117
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发表时间：
2020-11-17
影响因子：
11.1
通讯作者：
Liao, Dezhi
中科院分区：
文献类型：
--
作者：
Braun, Nicholas J.;Yao, Katherine R.;Liao, Dezhi
慢性创伤性脑病（CTE）与反复性创伤性脑损伤（TBI）相关，其特征为患者大脑出现认知衰退以及tau蛋白神经原纤维缠结（NFTs）。在此，我们提供了直接证据，表明细胞尺度的机械变形可引发神经元中tau异常和突触缺陷。通过计算机建模，我们发现CTE患者大脑中NFTs的早期病理位点，是受伤时发生高度变形的区域。仅与高应变速率变形相关的机械能，就能诱导培养的大鼠海马神经元中tau蛋白错误定位于树突棘并出现突触缺陷。这些细胞变化由tau蛋白过度磷酸化介导，可通过抑制糖原合成酶激酶-3β（GSK3β）和细胞周期蛋白依赖性激酶5（CDK5），或通过基因敲除tau蛋白来逆转。综上所述，这些研究结果确定了一条将神经元机械变形与tau介导的突触损伤直接联系起来的机制途径，并为对抗CTE提供了一条可能具有开发价值的治疗途径。
Chronic traumatic encephalopathy (CTE) is associated with re-peated traumatic brain injuries (TBI) and is characterized by cognitive decline and the presence of neurofibrillary tangles (NFTs) of the protein tau in patients' brains. Here we provide direct evidence that cell-scale mechanical deformation can elicit tau abnormalities and synaptic deficits in neurons. Using computational modeling, we find that the early pathological loci of NFTs in CTE brains are regions of high deformation during injury. The mechanical energy associated with high-strain rate deformation alone can induce tau mislocalization to dendritic spines and synaptic deficits in cultured rat hippocampal neurons. These cellular changes are mediated by tau hyperphosphorylation and can be reversed through inhibition of GSK3 beta and CDK5 or genetic deletion of tau. Together, these findings identify a mechanistic pathway that directly relates mechanical deformation of neurons to tau-mediated synaptic impairments and provide a possibly exploitable therapeutic pathway to combat CTE.