Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455.
Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455.
Proc Natl Acad Sci U S A. 2020 Nov 17;117(46):29069-29079. doi: 10.1073/pnas.2008306117. Epub 2020 Nov 2.
Chronic traumatic encephalopathy (CTE) is associated with repeated 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 GSK3β 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.
慢性创伤性脑病（CTE）与反复性创伤性脑损伤（TBI）相关，其特征是患者大脑中的认知能力下降和神经原纤维缠结（NFTs）的出现。在这里，我们提供了直接的证据表明细胞级别的机械变形可以在神经元中引发 tau 异常和突触缺失。通过计算建模，我们发现 CTE 大脑中 NFTs 的早期病理位置是损伤过程中变形较高的区域。单纯的高应变速率变形所产生的机械能就可以导致 tau 错误定位到树突棘和培养的大鼠海马神经元的突触缺失。这些细胞变化是通过 tau 过度磷酸化介导的，并且可以通过抑制 GSK3β 和 CDK5 或 tau 的基因缺失来逆转。总之，这些发现确定了一个机械途径，该途径将神经元的机械变形直接与 tau 介导的突触损伤联系起来，并为对抗 CTE 提供了一条可能可行的治疗途径。
