The possible prediction for the onset of Alzheimer's disease : lipoprotein-free Aβ

阿尔茨海默病发病的可能预测：无脂蛋白 Aβ

• 批准号: 14570597
• 负责人: MATSUBARA Etsuro
• 金额: $ 2.11万
• 依托单位: OKAYAMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570597/
• 关键词: Alzheimer's disease; Aβ; ELISA; melatonin; amyloid; transgenic mouse; 血液リポ蛋白非結合型Aβ; ダウン症候群; トランスジェニックマウス; 治療

To assess whether lipoproteins are physiologically able to balance and modulate the sAβ homeostasis in vivo, soluble Aβ levels in lipoprotein-depleted plasma were measured as a function of age in normal controls, Alzheimer's disease (AD) patients, and Down's syndrome (DS) cases. The reshaping of sAβ homeostasis, in particular the sAβ42-lipoprotein interaction, takes place over normal-60s, whereas mild AD patients appear to have impaired this anti-amyloidogenic mechanism resulting in a significant increase of lipoprotein-free sAβ42. Similar loss of function takes place in Down's syndrome patients. Lipoprotein-free sAβ remains significantly elevated from the presymptomatic through the symptomatic stages of the disease, and declines with the progression of the AD-like pathology. The dissociation of sAβ from lipoprotein-particles also occurs in brain parenchyma and the presence of soluble dimeric lipoprotein-free Aβ prior to its parenchymal deposition in AD brains would support the hypothe … More sis that functionally declined lipoproteins may be major determinants in the production of metabolic conditions leading to higher levels of sAβ species and cerebral amyloidosis. These data was corroborated with the analysis of pooled CSF soluble Aβ in normal control individual and AD via size-exclusion chromatography and ELISA. Lipoprotein-free sAβ in CSF was significantly decreased in AD, indicating that brain to CSF clearance of Lipoprotein-free sAβ can be impaired in AD and its failure, a pathological step in AD pathology.We also found that the administration of melatonin partially inhibited the expected time-dependent-elevation of Aβ-amyloidosis, reduced abnormal nitration of proteins, and increased survival in the treated transgenic mice model of AD. To clarify a potential physiological role of melatonin in AD pathogenesis, we have monitored the effect of this hormone on Aβ clearance in transgenic mice. It is relevant to note that melatonin has ability to upregulate Aβ clearance out of the brain. These results presented here suggest that melatonin can be explored as disease-modifying agents in AD. Less

为了评估脂蛋白是否能够在生理上平衡和调节体内sAβ稳态，在正常对照、阿尔茨海默病（AD）患者和唐氏综合征（DS）病例中，测量了脂蛋白耗尽血浆中可溶性Aβ水平作为年龄的函数。sAβ稳态的重塑，特别是sAβ42-脂蛋白相互作用，发生在正常-60岁，而轻度AD患者似乎已经损害了这种抗淀粉样蛋白形成机制，导致无脂蛋白sAβ42显著增加。类似的功能丧失也发生在唐氏综合症患者身上。无脂蛋白sAβ从症状前到疾病的症状阶段一直显著升高，并随着AD样病理的进展而下降。sAβ与脂蛋白颗粒的解离也发生在脑实质中，可溶性二聚体无脂蛋白Aβ在AD脑实质沉积之前的存在支持了AD脑中脂蛋白颗粒的低表达。 ...更多信息 认为功能下降的脂蛋白可能是导致较高水平sAβ物质和脑淀粉样变性的代谢条件产生的主要决定因素。通过分子排阻色谱和ELISA分析正常对照个体和AD中合并CSF可溶性Aβ，证实了这些数据。AD患者CSF中的无脂蛋白sAβ显著降低，表明AD患者脑至CSF的无脂蛋白sAβ清除率受损，这是AD病理学的一个病理步骤。我们还发现，给予褪黑激素部分抑制了预期的Aβ淀粉样变性的时间依赖性升高，减少了蛋白质的异常硝化，并增加了AD转基因小鼠模型的存活率。为了阐明褪黑激素在AD发病机制中的潜在生理作用，我们监测了该激素对转基因小鼠Aβ清除的影响。值得注意的是，褪黑激素具有上调Aβ清除出脑的能力。这些结果表明，褪黑激素可以探索作为AD的疾病修饰剂。少

项目成果

Yamashita T, Matsubara E, Nagano I, Shoji M, Abe K: "Bilateral extraocular muscle atrophy in myotonic dystrophy type 1."Neurology. (in press).

Yamashita T、Matsubara E、Nagano I、Shoji M、Abe K：“强直性肌营养不良 1 型双侧眼外肌萎缩”。神经病学。

Ikarashi Y, Matsubara E, et al.: "Decreased level of brain acetylcholine and memory disturbance in APPsw mice."Neurobiology of Aging. 25. 483-490 (2004)

Ikarashi Y、Matsubara E 等人：“APPsw 小鼠大脑乙酰胆碱水平降低和记忆障碍。”衰老神经生物学。

Kawarabayashi T, Shoji M, Younkin L, Wen-Lang L, Dickson DW, Murakami T, Matsubara E, Abe K, Ashe KH, Younkin SG: "Dimeric Aβ Rapidly Accumulates in Lipid Rafts Followed by ApoE and Phosphorylated Tau as Memory is Impaired in the Tg2576 Mouse Model of Alz

Kawarabayashi T、Shoji M、Younkin L、Wen-Lang L、Dickson DW、Murakami T、Matsubara E、Abe K、Ashe KH、Younkin SG：“当记忆受损时，二聚 Aβ 在脂筏中快速积累，随后是 ApoE 和磷酸化 Tau在阿尔茨海默症 Tg2576 小鼠模型中

Shizuka-Ikeda M, Matsubara E, Ikeda M, Kanai M, Tomidokoro Y, Ikeda Y, Watanabe M, Kawarabayashi T, Harigaya Y, Okamoto K, Maruyama K, Castano EM, St George-Hyslop P, Shoji M.: "Generation of amyloid beta protein from a presenilin-1 and betaAPP complex."B

Shizuka-Ikeda M、Matsubara E、Ikeda M、Kanai M、Tomidokoro Y、Ikeda Y、Watanabe M、Kawarabayashi T、Harigaya Y、Okamoto K、Maruyama K、Castano EM、St George-Hyslop P、Shoji M.：“一代”

Matsubara E, et al.: "Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer's disease."Journal of Neurochemistry. 85. 1101-1108 (2003)

Matsubara E 等人：“褪黑激素可提高阿尔茨海默病转基因模型的存活率并抑制氧化和淀粉样蛋白病理。”神经化学杂志。