Glöckner Frauke, Ohm Thomas G
From Clinical Cell and Neurobiology, Institute for Integrative Neuroanatomy, Charité, Universitätsmedizin Berlin, Berlin, Germany.
J Neuropathol Exp Neurol. 2014 Sep;73(9):846-54. doi: 10.1097/NEN.0000000000000103.
Epidemiologic and experimental data suggest the involvement of cholesterol metabolism in the development and progression of Alzheimer disease and Niemann-Pick type C disease, but not of frontotemporal dementias. In these 3 neurodegenerative diseases, however, protein tau hyperphosphorylation and aggregation into neurofibrillary tangles are observed. To elucidate the relationship between cholesterol and tau, we compared sterol levels of neurons burdened with neurofibrillary tangles with those of their unaffected neighbors using semiquantitative filipin fluorescence microscopy in mice expressing P301L mutant human tau (a well-described model of FTDP-17) and in P301L transgenic mice lacking apolipoprotein E (the major cholesterol transporter in the brain). Cellular unesterified cholesterol was higher in neurons affected by tau pathology irrespective of apolipoprotein E deficiency. This argues for an impact of tau pathology on cellular cholesterol homeostasis. We suggest that there is a bidirectional mode of action: Disturbances in cellular cholesterol metabolism may promote tau pathology, but tau pathology may also alter neuronal cholesterol homeostasis; once it is established, a vicious cycle may promote neurofibrillary tangle formation.
流行病学和实验数据表明，胆固醇代谢参与了阿尔茨海默病和尼曼-匹克C型病的发生和发展，但与额颞叶痴呆无关。然而，在这三种神经退行性疾病中，均观察到蛋白质tau过度磷酸化并聚集成神经原纤维缠结。为了阐明胆固醇与tau之间的关系，我们使用半定量的菲律宾菌素荧光显微镜，比较了表达P301L突变型人tau的小鼠（一种已充分描述的FTDP-17模型）和缺乏载脂蛋白E（大脑中主要的胆固醇转运蛋白）的P301L转基因小鼠中，负担有神经原纤维缠结的神经元与其未受影响的相邻神经元的固醇水平。无论载脂蛋白E是否缺乏，受tau病理影响的神经元中细胞游离胆固醇均较高。这表明tau病理对细胞胆固醇稳态有影响。我们认为存在一种双向作用模式：细胞胆固醇代谢紊乱可能促进tau病理，但tau病理也可能改变神经元胆固醇稳态；一旦形成，恶性循环可能会促进神经原纤维缠结的形成。
