Lei Peng, Ayton Scott, Appukuttan Ambili Thoppuvalappil, Volitakis Irene, Adlard Paul A, Finkelstein David I, Bush Ashley I
Oxidation Biology Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia.
Oxidation Biology Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia.
Neurobiol Dis. 2015 Sep;81:168-75. doi: 10.1016/j.nbd.2015.03.015. Epub 2015 Mar 18.
Iron accumulation and tau protein deposition are pathological features of Alzheimer's (AD) and Parkinson's diseases (PD). Soluble tau protein is lower in affected regions of these diseases, and we previously reported that tau knockout mice display motor and cognitive behavioral abnormities, brain atrophy, neuronal death in substantia nigra, and iron accumulation in the brain that all emerged between 6 and 12 months of age. This argues for a loss of tau function in AD and PD. We also showed that treatment with the moderate iron chelator, clioquinol (CQ) restored iron levels and prevented neuronal atrophy and attendant behavioral decline in 12-month old tau KO mice when commenced prior to the onset of deterioration (6 months). However, therapies for AD and PD will need to treat the disease once it is already manifest. So, in the current study, we tested whether CQ could also rescue the phenotype of mice with a developed phenotype. We found that 5-month treatment of symptomatic (13 months old) tau KO mice with CQ increased nigral tyrosine hydroxylase phosphorylation (which induces activity) and reversed the motor deficits. Treatment also reversed cognitive deficits and raised BDNF levels in the hippocampus, which was accompanied by attenuated brain atrophy, and reduced iron content in the brain. These data raise the possibility that lowering brain iron levels in symptomatic patients could reverse neuronal atrophy and improve brain function, possibly by elevating neurotrophins.
铁蓄积和tau蛋白沉积是阿尔茨海默病（AD）和帕金森病（PD）的病理特征。在这些疾病的受累区域，可溶性tau蛋白水平较低，我们之前报道tau基因敲除小鼠在6至12个月大时出现运动和认知行为异常、脑萎缩、黑质神经元死亡以及脑内铁蓄积。这表明在AD和PD中tau功能丧失。我们还表明，在恶化开始前（6个月）开始用中度铁螯合剂氯碘羟喹（CQ）治疗，可恢复12月龄tau基因敲除小鼠的铁水平，并预防神经元萎缩及随之而来的行为衰退。然而，AD和PD的治疗需要在疾病已经显现时进行治疗。因此，在当前研究中，我们测试了CQ是否也能挽救具有已发展表型的小鼠的表型。我们发现，对有症状的（13月龄）tau基因敲除小鼠进行5个月的CQ治疗可增加黑质酪氨酸羟化酶磷酸化（诱导活性）并逆转运动缺陷。治疗还逆转了认知缺陷并提高了海马体中的脑源性神经营养因子（BDNF）水平，这伴随着脑萎缩减轻和脑内铁含量降低。这些数据增加了一种可能性，即降低有症状患者的脑铁水平可能通过提高神经营养因子来逆转神经元萎缩并改善脑功能。
