Study of pathogenesis of Abeta amyloid deposits in Alzheimer's disease

阿尔茨海默病中 Abeta 淀粉样蛋白沉积的发病机制研究

• 批准号: 10832003
• 负责人: SHOJI Mikio
• 金额: $ 2.5万
• 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: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10832003/
• 关键词: Alzheimer's disease; Amyloid; Abeta 42; Aβ40; リポ蛋白結合型; リポ蛋白非結合型; 血液Aβ; Aβ; 脳Aβ; 脳脊髄液Aβ

To clarify the accumulation mechanism of physiological peptide, i.e., Abeta amyloid protein (Abeta) in Alzheimer's disease, studies described below were conducted.1) The levels of Abeta 40/42 of the brain and plasma in transgenic mice (PrP betaAPP751 NL+I, PrP presenilin-1 M146L, PrP presenilin-1 C410Y and APPsw mice) were evaluated showing nmol/g levels Abeta 40/42 were accumulated in the APPsw brain and fmol and pmol level increase of Abeta 40/42 were observed in the brain and plasma in all transgenic mice line.2) The age-related physiological alteration of Abeta 40/42 in CSF and plasma were observed in normal control subjects.3) The clinical usefulness of measurement of CSF tau and Abeta 40/42 is established for a diagnosic marker for AD by large scale multicenter study.4) The effect of apoE4 on advance of dementia and CSF tau concentrations were revealed.5) The amounts of Abeta 40/42 accumulation in the AD brain were nmol/g levels, but any Abeta accumulation was observed in control brains. Abeta 40 was detected in normal human urine.6) Plasma lipoprotein unbinding Abeta 40/42 was increased in sporadic AD and Down syndrome patients showing the levels of lipoprotein free Abeta40/42 as the possible diagnostic marker for AD and the important role of plasma lipoprotein for sequestration Abeta40/42.

为了阐明生理肽的积累机制，A β淀粉样蛋白（A β）在阿尔茨海默病中的作用，进行了下述研究。1）转基因小鼠脑和血浆中A β 40/42的水平（PrP β APP 751 NL+I，PrP早老素-1 M146 L，PrP早老素-1（C410 Y和APPsw小鼠）进行评价，显示出nmol/g水平的Abeta 40/在所有转基因小鼠系中，脑和血浆中均观察到Abeta 40/42的fmol和pmol水平增加。3）通过大规模多中心研究，建立了检测脑脊液tau蛋白和A β 40/42作为AD诊断指标的临床价值; 4）揭示了apoE 4对痴呆进展和脑脊液tau蛋白浓度的影响。AD脑中Abeta 40/42积累的量为nmol/g水平，但在对照脑中观察到任何Abeta积累。在正常人尿液中检测到Abeta 40。6）在散发性AD和唐氏综合征患者中血浆脂蛋白未结合Abeta 40/42增加，显示脂蛋白游离Abeta 40/42的水平作为AD的可能诊断标志物，以及血浆脂蛋白对于隔离Abeta 40/42的重要作用。

项目成果

Shizuka M, Ikeda Y, Watanabe M, Okamoto K, Shoji M, Ikegami T, Hayasaka K.: "A novel mutation of the myelin P(o) gene segregating Charcot-Marie-Tooth disease type 1B manifesting as trigeminal nerve thickening."J Neurol Neurosurg Psychiatry. 67. 250-1 (199

Shizuka M、Ikeda Y、Watanabe M、Okamoto K、Shoji M、Ikegami T、Hayasaka K.：“髓磷脂 P(o) 基因的一种新突变使 1B 型腓骨肌萎缩症分离，表现为三叉神经增厚。”

Kanai M, Shizuka M, Urakami K, Matsubara E, Harigaya Y, Okamoto K, Shoji M,: "Apolipoprotein E4 accelerates dementia and increases cerebrospinal fluid tau levels in Alzheimer's disease."Neurosci Lett. 267. 65-8 (1999)

Kanai M、Shizuka M、Urakami K、Matsubara E、Harigaya Y、Okamoto K、Shoji M：“载脂蛋白 E4 会加速阿尔茨海默氏病的痴呆并增加脑脊液 tau 水平。”Neurosci Lett。

Kanai M,Shouji M,et al: "Apolipoprotein E4 accelerates dementia and increases cerebrospinal fluid tau levels in Alzheimer's disease"Neurosci Lett.. 267. 65-68 (1999)

Kanai M、Shouji M 等人：“载脂蛋白 E4 加速阿尔茨海默氏病的痴呆并增加脑脊液 tau 水平”Neurosci Lett.. 267. 65-68 (1999)

Shoji M,Harigaya Y et al.: "Accumulation of amyloid β protein transgenic mice." Neurobiol Aging. 19. S59-63 (1998)

Shoji M、Harigaya Y 等人：“β 淀粉样蛋白转基因小鼠的积累。”19. S59-63 (1998)

Tomidokoro Y.Harigaya Y.Shoji: "Carboxylterminal fragments' of presenilin-lare closely relatea Metal to cytoskeletal abnormality in Alzheimer's brains." Biochem Biophys Res Commun. (in press). (1999)

Tomidokoro Y.Harigaya Y.Shoji：“早老素的羧基末端片段”与阿尔茨海默病大脑中的细胞骨架异常与金属密切相关。