Age-dependent induction of congophilic neurofibrillary tau inclusions in tau transgenic mice
Age-dependent induction of congophilic neurofibrillary tau inclusions in tau transgenic mice
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DOI：
10.1016/s0002-9440(10)63997-1
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发表时间：
2001-02-01
影响因子：
6
通讯作者：
Lee, VMY
中科院分区：
文献类型：
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作者：
Ishihara, T;Zhang, B;Lee, VMY
神经原纤维缠结(NFTs)是阿尔茨海默病(AD)及其相关的散发性和家族性tau病的神经病理学特征，在认知正常的人的海马体和内嗅皮层中也发现了与AD大脑中发现的相同的NFTs。为了在小鼠模型中总结年龄诱导的NFT形成，我们检查了12至24个月大的转基因(TG)小鼠，过度表达最小的人脑tau亚型，这些TG小鼠在包括海马体、杏仁核和内嗅觉皮质在内的几个大脑区域产生同嗜性tau包涵体。NFT样包涵体首先在18至20个月龄的TG小鼠中检测到，并通过与交叉的β-折叠片状结构(如刚果红、硫代黄素S)特异结合的组织化学染色检测到，此外，在超微结构上，这些病变包含直的tau细丝，包括鼠和人tau蛋白，而不包括其他细胞骨架蛋白(腿、神经细丝、微管)。分离的tau丝也从洗涤剂不溶的tau组分和脑中积累的不溶tau蛋白中以年龄依赖的方式被恢复。因此，人脑中最小的tau亚型的过度表达导致迟发性和年龄相关的同嗜性tau包涵体的形成，其性质类似于人类tau病的缠结，从而暗示衰老与纤维性tau包涵体的发病机制有关。
Intraneuronal filamentous tau inclusions such as neurofibrillary tangles (NFTs) are neuropathological hallmarks of Alzheimer's disease (AD) and related sporadic and familial tauopathies, NFTs identical to those found in AD brains have also been detected in the hippocampus and entorhinal cortex of cognitively normal individuals as they age. To recapitulate age-induced NFT formation in a mouse model, we examined 12- to 24-month-old transgenic (Tg) mice overexpressing the smallest human brain tau isoform, These Tg mice develop congophilic tau inclusions in several brain regions including the hippocampus, amygdala, and entorhinal cortex. NFT-like inclusions were first detected in Tg mice at 18 to 20 months of age and they were detected by histochemical dyes that bind specifically to crossed beta -pleated sheet structures (eg, Congo red, Thioflavin S), Moreover, ultrastructurally these lesions contained straight tau filaments comprised of both mouse and human tau proteins but not other cytoskeletal proteins leg, neurofilaments, microtubules). Isolated tau filaments were also recovered from detergent-insoluble tau fractions and insoluble tau proteins accumulated in brain in an age-dependent manner. Thus, overexpression of the smallest human brain tau isoform resulted in late onset and age-dependent formation of congophilic tau inclusions with properties similar to those in the tangles of human tauopathies, thereby implicating aging in the pathogenesis of fibrous tau inclusions.