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

为了阐明β淀粉样蛋白（Aβ）和神经原纤维缠结（NFT）在阿尔茨海默病（AD）大脑中积累的机制，我们首先检测了表达人类βAPP695ΔNL的APPsw小鼠，显示出大量的Aβ淀粉样变性和空间记忆缺陷（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。核心斑块取代了正常脑组织，导致神经元和突触的局灶性损失，并引起随后的病理，如神经突营养不良和过度磷酸化的tau蛋白的出现。然而，没有观察到NFT和神经元细胞死亡。接下来，我们产生了转基因小鼠（Tg），过表达与17号染色体相关的帕金森病额颞叶痴呆相关的人类4重复最长tau蛋白R406W突变体。这些小鼠在额前叶神经元细胞的胞浆和神经突中出现了广泛的tau积聚，更多的颞皮质、海马和杏仁核体伴有胶质细胞增生。电镜观察，累积的tau蛋白高度磷酸化，由直小管组成。糖原合成酶激酶3 β和细胞周期蛋白依赖性激酶5密切参与tau蛋白的磷酸化和积累。Western blot分析表明，萨科齐不溶性tau蛋白在大脑中沉积。他们表现出运动障碍和记忆力减退。这些发现表明，我们的Tau R406W小鼠将为测试未来的治疗药物和了解AD中a β积累引起的继发性牛头病的发病机制提供有用的模型。最后，我们将Tau R406W小鼠与APPsw小鼠杂交。双Tg和APPsw小鼠的Aβ淀粉样变性病理相似。Gallyas银染色显示，与tau R406W小鼠相比，双Tg小鼠海马的tau病理增强。这些发现提示，Aα淀粉样变可引起磷酸化tau蛋白积累、神经元丢失和记忆障碍等后续病理，治疗Aα淀粉样变对AD的治疗至关重要。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