Department of Biomedical Engineering, Minneapolis, Minnesota.
Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota.
Biophys J. 2021 Aug 17;120(16):3272-3282. doi: 10.1016/j.bpj.2021.07.011. Epub 2021 Jul 20.
Chronic traumatic encephalopathy is a neurodegenerative disease associated with repeated traumatic brain injury (TBI). Chronic traumatic encephalopathy is a tauopathy, in which cognitive decline is accompanied by the accumulation of neurofibrillary tangles of the protein tau in patients' brains. We recently found that mechanical force alone can induce tau mislocalization to dendritic spines and loss of synaptic function in in vitro neuronal cultures with random cell organization. However, in the brain, neurons are highly aligned, so here we aimed to determine how neuronal organization influences early-stage tauopathy caused by mechanical injury. Using microfabricated cell culture constructs to control the growth of neurites and an in vitro simulated TBI device to apply controlled mechanical deformation, we found that neuronal orientation with respect to the direction of a uniaxial high-strain-rate stretch injury influences the degree of tau pathology in injured neurons. We found that a mechanical stretch applied parallel to the neurite alignment induces greater mislocalization of tau proteins to dendritic spines than does a stretch with the same strain applied perpendicular to the neurites. Synaptic function, characterized by the amplitude of miniature excitatory postsynaptic currents, was similarly decreased in neurons with neurites aligned parallel to stretch, whereas in neurons aligned perpendicular to stretch, it had little to no functional loss. Experimental injury parameters (strain, strain rate, direction of stretch) were combined with a standard viscoelastic solid model to show that in our in vitro model, neurite work density during stretch correlates with tau mislocalization. These findings suggest that in a TBI, the magnitude of brain deformation is not wholly predictive of neurodegenerative consequences of TBI but that deformation relative to local neuronal architecture and the neurite mechanical energy during injury are better metrics for predicting trauma-induced tauopathy.
慢性创伤性脑病是一种与反复性创伤性脑损伤（TBI）相关的神经退行性疾病。慢性创伤性脑病是一种tau 病，在这种疾病中，认知能力下降伴随着患者大脑中 tau 蛋白神经原纤维缠结的积累。我们最近发现，仅机械力就可以诱导 tau 蛋白向树突棘的错误定位，并导致体外神经元培养物中突触功能丧失，而这些神经元培养物中的细胞组织是随机的。然而，在大脑中，神经元的排列是高度有序的，因此，我们旨在确定神经元组织如何影响由机械损伤引起的早期 tau 病。我们使用微加工细胞培养结构来控制神经突的生长，并使用体外模拟 TBI 设备施加受控的机械变形，发现神经元相对于单轴高应变速率拉伸损伤的方向会影响受伤神经元中 tau 病理学的程度。我们发现，与沿神经突取向施加的相同应变相比，平行于神经突取向施加的机械拉伸会导致 tau 蛋白更大程度地向树突棘错误定位。以微小兴奋性突触后电流幅度为特征的突触功能在平行于拉伸方向排列的神经元中也同样降低，而在垂直于拉伸方向排列的神经元中，其功能丧失很少或没有。实验性损伤参数（应变、应变速率、拉伸方向）与标准粘弹性固体模型相结合，表明在我们的体外模型中，拉伸过程中的神经突功密度与 tau 蛋白错误定位相关。这些发现表明，在 TBI 中，大脑变形的幅度不能完全预测 TBI 的神经退行性后果，而变形相对于局部神经元结构和损伤过程中的神经突机械能是预测创伤性 tau 病的更好指标。
