Rametti A, Esclaire F, Yardin C, Cogné N, Terro F
Unité de Neurobiologie Cellulaire, EA 3842, Homéostasie Cellulaire et Pathologies, Faculté de Médecine, Université de Limoges, 87025 Limoges, France.
Neurosci Lett. 2008 Mar 21;434(1):93-8. doi: 10.1016/j.neulet.2008.01.034. Epub 2008 Jan 19.
In tauopathies such as Alzheimer's disease (AD), the moleccular mechanisms of tau protein agregation into neurofibrillary tangles (NFTs) and their contribution to neurodegeneration are not fully understood. Recent studies indirectly demonstrated that tau, regardless of its aggregation, might represent a key mediator of neurodegeneration, especially that induced by the amyloid (Abeta) pathology. Lithium is a medication for bipolar mood disorders. Its therapeutic mechanism of action remains unclear, in part because of the large number of biochemical effects attributed to lithium. Since lithium directly inhibits glycogen synthase kinase-3beta (GSK3beta), a key enzyme involved in tau phosphorylation, it was suggested that the therapeutic use of lithium could be expanded from mood disorders to neurodegenerative conditions. Lithium has been also reported to protect cultured neurons against Abeta toxicity, and to prevent NFTs accumulation and cognitive impairments in transgenic models of tauopathies. However, the exact mechanism of neuroprotection provided by lithium remains unknown. Here, we show that exposure of cultured cortical neurons to lithium decreased tau protein levels. This decrease was not linked to the activation of proteolytic processes including calpains, caspases and proteasome or to neuronal loss, but was rather associated with a reduction in tau mRNA levels. Moreover, prior exposure to lithium, at concentrations effective in reducing tau protein levels, markedly reduced pre-aggregated Abeta-induced neuronal apoptosis. Our findings raise the possibility that lithium could exert its neuroprotective effect against Abeta toxicity through the downregulation of tau proteins and that, at least, by acting at the level of tau mRNA.
在诸如阿尔茨海默病（AD）等tau蛋白病中，tau蛋白聚集成神经原纤维缠结（NFTs）的分子机制及其对神经退行性变的作用尚未完全明确。最近的研究间接表明，tau蛋白无论是否聚集，都可能是神经退行性变的关键介质，尤其是由淀粉样蛋白（Aβ）病理引起的神经退行性变。锂是一种用于治疗双相情感障碍的药物。其治疗作用机制尚不清楚，部分原因是锂具有大量的生化效应。由于锂直接抑制糖原合酶激酶-3β（GSK3β），这是一种参与tau蛋白磷酸化的关键酶，因此有人提出锂的治疗用途可从情绪障碍扩展到神经退行性疾病。也有报道称锂可保护培养的神经元免受Aβ毒性影响，并可预防tau蛋白病转基因模型中NFTs的积累和认知障碍。然而，锂提供神经保护的确切机制仍不清楚。在此，我们表明，将培养的皮质神经元暴露于锂可降低tau蛋白水平。这种降低与包括钙蛋白酶、半胱天冬酶和蛋白酶体在内的蛋白水解过程的激活或神经元丢失无关，而是与tau mRNA水平的降低有关。此外，预先以有效降低tau蛋白水平的浓度暴露于锂，可显著减少预聚集Aβ诱导的神经元凋亡。我们的研究结果提示，锂可能通过下调tau蛋白发挥其对Aβ毒性的神经保护作用，并且至少在tau mRNA水平起作用。
