Mechanism of accumulation of amyloid and neurofibrillary tangles in Alzheimer's disease brain

为了阐明淀粉样蛋白β蛋白(Aβ)和神经原纤维缠结(NFT)在阿尔茨海默病(AD)脑中积累的机制，我们首先研究了表达人βAPP695ΔNL的APPsw小鼠，发现Aβ淀粉样变性和空间记忆障碍(K Hsiao等)。《科学》(1996)。我们在APPsw小鼠的大脑中发现了由N-端和C-端修饰的各种Aβ物种组成的核心、弥漫性斑块和淀粉样血管病变。这些核心斑块取代了正常的脑组织，导致神经元和突触的局灶性丢失，并导致随后的病理，如营养不良的神经元突起和过度磷酸化的tau的出现。然而，没有观察到NFT和神经细胞死亡。接下来，我们产生了过量表达R406W突变形式的人4重复最长tau的转基因小鼠(TG)，这些小鼠与17号染色体连锁的帕金森痴呆相关。这些小鼠在额叶-t…的神经细胞胞浆和神经突起中广泛积聚tau大脑皮质、海马体和杏仁体较多，伴有胶质细胞增多症。电子显微镜下可见聚集的tau高度磷酸化，并由直管组成。糖原合成酶激酶3β和细胞周期蛋白依赖性激酶5与tau的磷酸化和蓄积密切相关。Western印迹分析显示肌糖不溶性tau沉积在脑内。他们表现出运动障碍和记忆力丧失。这些结果表明，我们的Tau R406W小鼠将为测试未来的治疗药物和了解Aβ积聚在AD中引起的继发性变态反应的发病机制提供一个有用的模型。在双甘油三酯和APPsw小鼠中，Aβ淀粉样变性的病理相似。Galyas银染显示，与Tau R406W小鼠相比，双TG组小鼠海马区tau病理增强。这些发现表明，Aα淀粉样变性会导致随后的病理改变，如磷酸化tau蛋白积聚、神经元丧失和记忆障碍，治疗Aα淀粉样变性是治愈AD的关键。较少

To clarify the mechanism of accumulation of amyloid β protein (Aβ) and neurofibrillary tangles (NFT) in brains of Alzheimer's disease (AD), we first examined APPsw mice expressing human βAPP695ΔNL demonstrating substantial Aβ amyloidosis and spatial memory deficit (K Hsiao et al. Science 1996). We found cored, diffuse plaques and amyloid angiopathy composed of various Aβ species with N- and C-terminal modifications in the brain of APPsw mice. The cored plaques substituted normal brain tissues with focal loss of neurons and synapses, and caused subsequent pathology such as dystrophic neurites and appearance of hyperphosphorylated tau. However, neither NFT nor neuronal cell death was observedNext, we have generated transgenic mice (Tg) overexpressing the R406W mutant form of human 4-repeat longest tau associated with fronto-temporal dementia with parkinsonism linked to chromosome 17. These mice developed widespread tau accumulation in cytoplasma and neurites of neuronal cells in fronto-t … More emporal cortex, hippocampus and amygdaloid body accompanied by gliosis. Accumulated tau was highly phosphorylated, and composed of straight tubules by electron microscopy. Glycogen synthase kinase 3 β and cyclin-dependent kinase 5 were closely involved in phosphorylation and accumulation of tau. Western blot analysis demonstrated sarkosyl insoluble tau deposited in brains. They showed motor disturbance and memory loss. These findings demonstrate that our Tau R406W mice will provide a useful model for testing future therapeutic agents and understanding the pathogenesis of secondary tauopathies induced by Aβ accumulation in AD.Finally, we crossed Tau R406W mice with APPsw mice. The pathology of Aβ amyloidosis was similar in both double Tg and APPsw mice. Gallyas silver-staining showed enhanced tau pathology in the hippocampus of double Tg relative to Tau R406W mice. These findings suggest that Aα amyloidosis causes subsequent pathology such as accumulation of phosphorylated tau, neuronal loss and memory disturbance, and that it is most important to treat Aα amyloidosis for cure of AD. Less