Suppression of Cl^- -ATPase activity in Alzheimer's disease brain

阿尔茨海默病脑中 Cl^--ATPase 活性的抑制

• 批准号: 16500248
• 负责人: HATTORI Naoki
• 金额: $ 2.37万
• 依托单位: Kansai Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16500248/
• 关键词: Cl^- -ATPase; amyloid β; chloride; Na-K ATPase; Alzheimer's disease; Cl^--ATPase; ホノキオール

Cl^- -ATPase enables the inhibitory neurotransmission by GABA by keeping the intracellular chloride concentration low. We previously reported that Cl^- -ATPase activity decreased in Alzheimer's disease brains and that low dose amyloid β(Aβ) inhibited Cl^- -ATPase activity leading to the elevation of intracellular chloride levels. In the present study, we investigated the effects of Aβ on Cl^- -ATPase activity in lymphocytes which are easily obtained from patients to see if the Cl^- -ATPase activity in lymphocytes reflects that of brains.[Materials and Methods]Effects Aβ on Cl^- -ATPase and Na-K ATPase activities, and on cell viability were examined in T-cell derived human leulemic cell line (Jurkat), myeloid cell derived human leukemic cell line (HL-60) and human peripheral lymphocytes. The cells were cultured in RPMI1640 containing 10% FCS with or without Aβ 25-35 (1μM) or Aβ 1-42 (100 nM), or 20μM quercetin as a PI4 kinase inhibitor or 0.05μM wartmannin as a PI3 kinase inhibitor.[Res … More ults]Membrane fractions from leukemic cell lines showed Cl^- -ATPase and Na-K ATPase activities. In peripheral blood from healthy volunteers, Cl^- -ATPase activity was detected in lymphocytes and neutrophils but not in red blood cells, while Na-K-ATPase activity was observed in all cells. Aβ 25-35 (1μM) or Aβ 1-42 (100 nM) significantly reduced Cl^- -ATPase in lymphocytes and had a tendency to decrease Na-K-ATPase activity. PI4 kinase inhibitor, 20μM quercetin significantly reduced Cl^- -ATPase, while PI3 kinase inhibitor, 0.5μM wartmannin did not alter the activity.[Discussion]The present study showed that Cl^- -ATPase was detectable in human lymphocytes and the activity was inhibited by Aβ and PI4 kinase inhibitor as observed in brains, suggesting that the same mechanisms are involved for the inhibition and that the effects of Aβ on brains can be reflected in those on lymphocytes which are easily obtainable. Measurement of Cl^- -ATPase in lymphocytes may possibly be used for early diagnosis of Alzheimer's disease. Less

Cl^- -ATPase 通过保持细胞内较低的氯化物浓度来实现 GABA 的抑制性神经传递。我们之前报道，阿尔茨海默病大脑中的 Cl^- -ATPase 活性降低，低剂量的淀粉样蛋白 β(Aβ) 抑制 Cl^- -ATPase 活性，导致细胞内氯离子水平升高。在本研究中，我们研究了Aβ对从患者体内容易获得的淋巴细胞中Cl^--ATP酶活性的影响，以了解淋巴细胞中Cl^--ATP酶活性是否反映了大脑的活性。[材料和方法]在T细胞衍生的人白血病细胞系（Jurkat）中检查了Aβ对Cl^--ATP酶和Na-K ATP酶活性以及细胞活力的影响， 骨髓细胞衍生的人白血病细胞系 (HL-60) 和人外周淋巴细胞。细胞在含有 10% FCS 的 RPMI1640 中培养，含或不含 Aβ 25-35 (1μM) 或 Aβ 1-42 (100 nM)，或 20μM 槲皮素（作为 PI4 激酶抑制剂）或 0.05μM 沃曼宁（作为 PI3 激酶抑制剂）。[Res … More ults]来自白血病细胞系的膜组分显示 Cl^- -ATP酶和 Na-K ATP酶活性。在健康志愿者的外周血中，在淋巴细胞和中性粒细胞中检测到Cl^--ATP酶活性，但在红细胞中未检测到Cl^--ATP酶活性，而在所有细胞中都观察到Na-K-ATP酶活性。 Aβ 25-35 (1μM) 或 Aβ 1-42 (100 nM) 显着降低淋巴细胞中的 Cl^--ATP 酶，并具有降低 Na-K-ATP 酶活性的趋势。 PI4激酶抑制剂20μM槲皮素显着降低Cl^--ATPase的活性，而PI3激酶抑制剂0.5μM沃特曼宁则没有改变其活性。[讨论]本研究表明，在人淋巴细胞中可检测到Cl^--ATPase，而在大脑中观察到Cl^--ATPase的活性被Aβ和PI4激酶抑制剂抑制，这表明相同的机制 Aβ 对大脑的影响可以反映在对淋巴细胞的影响上，而淋巴细胞很容易获得。淋巴细胞中Cl--ATP酶的测量可能用于阿尔茨海默病的早期诊断。较少的

项目成果

Abxiolytic agent, dihydrohonokiol-B, recovers amyloid β protein-induce neurotoxicity in cultured rat hippocampal neurons.

抗焦虑剂二氢和厚朴酚-B 可恢复培养的大鼠海马神经元中淀粉样蛋白 β 蛋白诱导的神经毒性。

• 发表时间: 2005
• 期刊: Neuroscience Letters 384
• 作者: Bing Liu;Naoki Hattori et al.
• 通讯作者: Naoki Hattori et al.

Expression and roles of Cl- channel ClC-5 in cell cycles of myeloid cells

• DOI: 10.1016/j.bbrc.2004.03.036
• 发表时间: 2004-04-23
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Jiang, BH;Hattori, N;Inagaki, C
• 通讯作者: Inagaki, C

Immunoglobulin G subclasses and prolactin (PRL) isoforms in macroprolactinemia due to anti-PRL autoantibodies

• DOI: 10.1210/jc.2004-1600
• 发表时间: 2005-05-01
• 期刊: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
• 影响因子: 5.8
• 作者: Hattori, N;Ikekubo, K;Inagaki, C
• 通讯作者: Inagaki, C

γ aminobutyric acid (GABA)-C receptor stimulation increases prolactin (PRL) secretion in rat anterior pituitary cells.

γ 氨基丁酸 (GABA)-C 受体刺激会增加大鼠垂体前叶细胞中催乳素 (PRL) 的分泌。

• 发表时间: 2006
• 期刊: Biochemical Pharmacology (in press)
• 作者: Yasuhisa Nakayama;Naoki Hattori et al.
• 通讯作者: Naoki Hattori et al.

Effects of growth hormone on the differentiation of mouse B-lymphoid precursors.

生长激素对小鼠 B 淋巴前体细胞分化的影响。

• 发表时间: 2005
• 期刊: J Pharmacol Sci 97
• 作者: Sumita K;Hattori N;Inagaki C
• 通讯作者: Inagaki C