Ishihara T, Zhang B, Higuchi M, Yoshiyama Y, Trojanowski J Q, Lee V M
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Am J Pathol. 2001 Feb;158(2):555-62. doi: 10.1016/S0002-9440(10)63997-1.
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 (eg, 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.
神经元内丝状tau包涵体，如神经原纤维缠结（NFTs），是阿尔茨海默病（AD）以及相关散发性和家族性tau蛋白病的神经病理学特征。随着年龄增长，在认知正常个体的海马体和内嗅皮质中也检测到了与AD大脑中发现的相同的NFTs。为了在小鼠模型中重现年龄诱导的NFT形成，我们研究了过表达最小人类脑tau异构体的12至24月龄转基因（Tg）小鼠。这些Tg小鼠在包括海马体、杏仁核和内嗅皮质在内的几个脑区中出现嗜刚果红性tau包涵体。NFT样包涵体在18至20月龄的Tg小鼠中首次被检测到，并且通过与交叉β折叠片层结构特异性结合的组织化学染料（如刚果红、硫黄素S）检测到。此外，在超微结构上，这些病变包含由小鼠和人类tau蛋白组成的直tau丝，但不包含其他细胞骨架蛋白（如神经丝、微管）。还从去污剂不溶性tau组分中回收了分离的tau丝，并且脑中不溶性tau蛋白以年龄依赖性方式积累。因此，最小人类脑tau异构体的过表达导致了嗜刚果红性tau包涵体的迟发性和年龄依赖性形成，其性质与人类tau蛋白病缠结中的性质相似，从而表明衰老在纤维状tau包涵体的发病机制中起作用。
