第49回日本神経学会総会
＜シンポジウム2-4＞神経変性疾患研究の焦点―新たな病的因子の登場と臨床への展望―
神経変性と炎症：FTDP-17モデルマウスをもちいて
吉山 容正
国立病院機構千葉東病院神経内科〔〒260-8712 千葉市中央区仁戸名町679〕
Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and related tauopathies, and the discovery of mutations in the tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) constitutes convincing evidence that tau proteins play a key role in the pathogenesis of neurodegenerative disorders. To investigate the pathomechanism of tauopathies, we generated and studied P301S mutant human tau transgenic mice (line PS19). Filamentous tau lesions developed in PS19 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 PS19 mice before fibrillary tau tangles emerged. Prominent microglial activation and proinflammatory cytokine expressions in neurons also preceded tangle formation. Importantly, immunosuppression of young PS19 mice with FK506 attenuated tau pathology, thereby linking neuroinflammation to early progression of tauopathies. Recently, an anti-inflammatory function of acetylcholine (ACh) has been reported, suggesting that synaptic dysfunction might accelerate neuroinflammatory reaction by depletion of ACH. To investigate this, we administered donepezil (DZ), an ACh-esterase inhibitor, and trihexiphenidyl (TP), an anti-cholinergic agent to PS19 mice. Interestingly, DZ ameliorated but TP deteriorated microglial activation, tau pathology and neuronal loss, indicating the ACh level in the brain might play roles in not only neurotransmission, but also suppressing neuroinflammation in the brain.
Full Text of this Article in Japanese PDF (191K)
(臨床神経, 48：910−912, 2008)
key words：神経変性, 炎症, 17番染色体に関連する前側頭型認知症とパーキンソニズム, タウ蛋白, 遺伝子導入マウス
（受付日：2008年5月16日）
