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

阿尔茨海默病大脑中淀粉样蛋白和神经原纤维缠结的积累机制

• 批准号: 12670593
• 负责人: HARIGAYA Yasuo
• 金额: $ 2.37万
• 依托单位: Gunma University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670593/
• 关键词: Alzheimer's disease; Amyloid β protein; Aβ amyloidosis; Neurofibrillary tangle; Tau; Transgenic mice

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

为了阐明阿尔茨海默病（AD）大脑中β淀粉样蛋白（Aβ）和神经原纤维缠结（NFT）积累的机制，我们首先检查了表达人类βAPP695ΔNL的APPsw小鼠，显示出严重的Aβ淀粉样变性和空间记忆缺陷（K Hsiao等人，Science 1996）。我们在 APPsw 小鼠的大脑中发现了由具有 N 端和 C 端修饰的各种 Aβ 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，并导致随后的病理学，例如营养不良的神经突和过度磷酸化的 tau 蛋白的出现。然而，既没有观察到 NFT，也没有观察到神经元细胞死亡接下来，我们培育了转基因小鼠 (Tg)，其过表达人类 4 重复最长 tau 的 R406W 突变形式，该突变形式与 17 号染色体相关的额颞叶痴呆和帕金森病相关。这些小鼠在额颞叶神经元细胞的细胞质和神经突中出现了广泛的 tau 积累……更多 皮质、海马体和杏仁体伴有神经胶质增生。电子显微镜观察发现，积累的tau蛋白高度磷酸化，由直管组成。糖原合酶激酶3β和细胞周期蛋白依赖性激酶5与tau蛋白的磷酸化和积累密切相关。蛋白质印迹分析表明，肌氨酸不溶性 tau 蛋白沉积在大脑中。他们表现出运动障碍和记忆丧失。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 Aβ 积累诱导的继发性 tau 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 小鼠和 APPsw 小鼠的 Aβ 淀粉样变性病理学相似。 Gallyas 银染色显示，相对于 Tau R406W 小鼠，双 Tg 小鼠海马中的 tau 病理学增强。这些发现表明，Aα淀粉样变性会引起磷酸化tau蛋白积累、神经元丢失和记忆障碍等后续病理，并且治疗Aα淀粉样变性对于治愈AD来说是最重要的。较少的

项目成果

Shizuka-Ikeda M, Harigaya Y, Shoji M et al.: "Generation of Amyloid β protein from a Presenilin-1 and βAPP complex"Biocem Biophys Res Commun. (In press).

Shizuka-Ikeda M、Harigaya Y、Shoji M 等人：“从 Presenilin-1 和 βAPP 复合物生成淀粉样 β 蛋白”Biocem Biophys Res Commun。

Paganelli AR, Shoji M, et al.: "The Alzheimer-related gene presenilin-1 facilitates sonic hedgehog expression in Xenopus primary neurogenesis"Mech Dev.. 107(1-2). 119-31 (2001)

Paganelli AR、Shoji M 等人：“阿尔茨海默病相关基因 presenilin-1 促进非洲爪蟾初级神经发生中音刺猬的表达”Mech Dev.. 107(1-2)。

Murakami T, Shoji M, et al.: "Impaired retrograde axonal transport of adenovirus-mediated E. coli LacZ gene in the mice carrying mutant SOD1 gene"Neurosci Lett.. 308(3). 49-52 (2001)

Murakami T、Shoji M 等人：“携带突变 SOD1 基因的小鼠中腺病毒介导的大肠杆菌 LacZ 基因的逆行轴突运输受损”Neurosci Lett.. 308(3)。

Takenoshita H, Harigaya Y, Shoji M, et al.: "Presynaptic inhibition of celebellar GABAergic transmission by glutamate decarboxylase autoantibodies in progressive cerebellar ataxia"J Neurol Neuro surg Psychiatry. 70(3). 386-389 (2001)

Takenoshita H、Harigaya Y、Shoji M 等人：“进行性小脑共济失调中谷氨酸脱羧酶自身抗体对小脑 GABA 能传递的突触前抑制”J Neurol 神经外科精神病学。

東海林幹夫: "アルツハイマー病のすべて(水澤英洋 編)"星和書店. 300-316 (2000)

东海林干雄：“关于阿尔茨海默病的一切（水泽秀宏编辑）”《清和书店》300-316（2000）。