Tajes Marta, Gutierrez-Cuesta Javier, Folch Jaume, Ferrer Isidre, Caballero Beatriz, Smith Mark A, Casadesus Gemma, Camins Antoni, Pallás Mercé
Unitat de Farmacologia, Facultat de Farmácia Institut de Biomedicina Universitat de Barcelona, Nucli Universitari de Pedralbes, Barcelona, Spain.
J Neuropathol Exp Neurol. 2008 Jun;67(6):612-23. doi: 10.1097/NEN.0b013e3181776293.
Lithium modulates glycogen synthase kinase 3beta (GSK-3beta), a kinase involved in Alzheimer disease-related tau pathology. To investigate mechanisms of aging and the potential therapy of lithium in neurodegenerative disease, we treated senescence-accelerated mouse (SAM)P8 mice, a murine model of senescence, and mice of the control SAMR1 strain with lithium. The treatment reduced hippocampal caspase 3 and calpain activation, indicating that it provides neuroprotection. Lithium also reduced both the levels and activity of GSK-3beta and the activity of cyclin-dependent kinase 5 and reduced hyperphosphorylation of 3 different phosphoepitopes of tau: Ser199, Ser212, and Ser396. In lithium-treated primary cultures of SAMP8 and SAMR1 cerebellar neurons, there was a marked reduction in protease activity mediated by calpain and caspase 3. Both lithium and SB415286, a specific inhibitor of GSK-3beta, reduced apoptosis in vitro. Taken together, these in vivo and in vitro findings of lithium-mediated reductions in GSK-3beta and cyclin-dependent kinase 5 activities, tau phosphorylation, apoptotic activity, and cell death provide a strong rationale for the use of lithium as a potential treatment in neurodegenerative diseases.
锂可调节糖原合酶激酶3β（GSK - 3β），这是一种与阿尔茨海默病相关的tau蛋白病理过程有关的激酶。为了研究衰老机制以及锂在神经退行性疾病中的潜在治疗作用，我们用锂处理了衰老加速小鼠（SAM）P8品系小鼠（一种衰老的小鼠模型）和对照SAMR1品系小鼠。该处理降低了海马体中半胱天冬酶3和钙蛋白酶的激活，表明它具有神经保护作用。锂还降低了GSK - 3β的水平和活性、细胞周期蛋白依赖性激酶5的活性，并减少了tau蛋白3个不同磷酸化表位（Ser199、Ser212和Ser396）的过度磷酸化。在用锂处理的SAMP8和SAMR1小脑神经元原代培养物中，钙蛋白酶和半胱天冬酶3介导的蛋白酶活性显著降低。锂和GSK - 3β的特异性抑制剂SB415286在体外均能减少细胞凋亡。综上所述，这些体内和体外研究结果表明，锂介导的GSK - 3β和细胞周期蛋白依赖性激酶5活性降低、tau蛋白磷酸化、凋亡活性及细胞死亡减少，为锂作为神经退行性疾病的潜在治疗药物提供了有力的理论依据。
