Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA.
Transl Psychiatry. 2017 Dec 18;7(12):1288. doi: 10.1038/s41398-017-0017-2.
Neurodegenerative tauopathies are characterized by pathological accumulation of highly phosphorylated isoforms of tau protein, which leads to progressive neuronal loss. Neuroinflammation often accompanies tau-driven diseases; however, the direct role of neuroinflammation in tauopathies remains unknown. The 5-lipoxygenase (5LO) is a pro-inflammatory enzyme, which produces several bioactive metabolites and is widely expressed in the central nervous system. Previously, our group showed that 5LO influences the Alzheimer's disease (AD) phenotype of APP transgenic mice as well as a mouse model with plaques and tangles. However, whether this protein directly modulates tau phosphorylation and subsequent neuropathology remains to be fully investigated. In the current study, we provide evidence for an age-dependent and region-specific upregulation of the 5LO pathway (protein, message and activity) in a transgenic mouse model of tauopathy, the P301S line. In addition, we demonstrate that genetic deletion of 5LO in this mouse model results in significant memory improvement, reduces tau phosphorylation at specific epitopes as well as neuroinflammation and rescues synaptic pathology. In vitro studies confirmed that 5LO directly modulates tau phosphorylation at the same epitopes as for the brain tissues. Taken together, our data reveal an active involvement of the 5LO pathway in the development of the tauopathy phenotype and provide strong support to the hypothesis that this enzymatic protein should be considered a novel and viable therapeutic target for the treatment of human tauopathy.
神经退行性 tau 病的特征是 tau 蛋白的高度磷酸化异构体的病理性积累，导致进行性神经元丧失。神经炎症常伴随着 tau 驱动的疾病；然而，神经炎症在 tau 病中的直接作用尚不清楚。5-脂氧合酶（5LO）是一种促炎酶，可产生几种生物活性代谢物，并广泛表达于中枢神经系统。先前，我们的研究小组表明 5LO 影响 APP 转基因小鼠的阿尔茨海默病（AD）表型以及具有斑块和缠结的小鼠模型。然而，这种蛋白质是否直接调节 tau 磷酸化及其随后的神经病理学仍有待充分研究。在目前的研究中，我们提供了证据表明，在 tau 病的转基因小鼠模型 P301S 线中，5LO 途径（蛋白、信使和活性）存在年龄依赖性和区域特异性上调。此外，我们证明在该小鼠模型中遗传缺失 5LO 会导致显著的记忆改善，减少特定表位的 tau 磷酸化以及神经炎症和挽救突触病理学。体外研究证实 5LO 可直接调节与脑组织相同表位的 tau 磷酸化。总之，我们的数据揭示了 5LO 途径在 tau 病表型发展中的积极参与，并为该酶蛋白应被视为人类 tau 病治疗的一种新的可行治疗靶点的假设提供了有力支持。
