Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model
Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model
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DOI：
10.1016/j.neuron.2007.01.010
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发表时间：
2007-02-01
期刊：
影响因子：
16.2
通讯作者：
Lee, Virginia M. -Y.
中科院分区：
文献类型：
--
作者：
Yoshiyama, Yasumasa;Higuchi, Makoto;Lee, Virginia M. -Y.
丝状tau包涵体是阿尔茨海默病(AD)和相关tau病的特征，但更早的病理可能预示着疾病的发生。为了研究这一点，我们研究了野生型和P301S突变的人tau转基因(TG)小鼠。P301 S转基因小鼠6个月龄时出现丝状tau病变，9-12个月龄时逐渐积累，伴随着显著的神经元丢失以及海马区和内嗅区皮质萎缩。值得注意的是，3月龄P301S转基因小鼠在出现纤维tau缠结之前，就已经检测到了海马区突触丢失和突触功能受损。突出的小胶质细胞活化也先于缠结形成。重要的是，携带FK506FK506的年轻P301 S TG小鼠的免疫抑制减轻了tau的病理，延长了寿命，从而将神经炎症与tau病的早期进展联系起来。因此，海马区突触病理和小胶质细胞增多症可能是神经退行性疾病的最早表现，而取消tau诱导的小胶质细胞激活可以延缓这些疾病的进展。
Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and related tauopathies, but earlier pathologies may herald disease onset. To investigate this, we studied wild-type and P301S mutant human tau transgenic (Tg) mice. Filamentous tau lesions developed in P301 S Tg mice at 6 months of age, and progressively accumulated in association with striking neuron loss as well as hippocampal and entorhinal cortical atrophy by 9-12 months of age. Remarkably, hippocampal synapse loss and impaired synaptic function were detected in 3 month old P301S Tg mice before fibrillary tau tangles emerged. Prominent microglial activation also preceded tangle formation. Importantly, immunosuppression of young P301 S Tg mice with FK506 attenuated tau pathology and increased lifespan, thereby linking neuro-inflammation to early progression of tauopathies. Thus, hippocampal synaptic pathology and microgliosis may be the earliest manifestations of neurodegenerative tauopathies, and abrogation of tau-induced microglial activation could retard progression of these disorders.