Modulation of β-amyloid and phosphorylated tau production by statin

他汀类药物调节 β-淀粉样蛋白和磷酸化 tau 蛋白的产生

• 批准号: 18590930
• 负责人: IKEUCHI Takeshi
• 金额: $ 2.58万
• 依托单位: Niigata University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590930/
• 关键词: Alzheimer disease; cholesterol; statin; amyloid precursor protein; tau; 認知症; 脳神経疾患; 神経科学; 脂質; 薬理学

Disease-modifying therapy has not been established in Alzheimer disease, in which ardinal pathological features include the accumulation of β-amyloid(Aβ) and phosphorylated tau forming senile plaque and neurofibrillary tangles, respectively. Previous epidemiological studies have suggested there is close link between impaired cholesterol metabolism and development of Alzheimer disease. Furthermore, amyloidogenesis occurs in cholesterol-rich membrane domains. Statins that inhibit cholesterol biosynthesis and have potential other multiple actions called pleiotropic effects, are the most widely used cholesterol-lowering agents. TheyIn this study, I investigated the effects of stain on modulation of β-amyloid and phosphorylated tau production using culture cells. SHSY-5Y and Neuro2a cells that stably express either amyloid precursor protein (APP) or tau were initially established for further assay. When cells were incubated with statin, the levels of full-length APP and APP C-terminal fragments were elevated. At high concentration of statin, Aβ42/40 ratio was markedly increased. Total and phosphorylated tau levels were apparently unaffected by statin treatment. These results suggest that cell-permeable statin have an effect on APP metabolism.

阿尔茨海默病的主要病理特征包括β-淀粉样蛋白（Aβ）和磷酸化tau蛋白的积累，分别形成老年斑和神经元缠结，但尚未建立疾病改善治疗。以往的流行病学研究表明，胆固醇代谢受损与阿尔茨海默病的发展密切相关。此外，淀粉样蛋白生成发生在富含胆固醇的膜结构域中。他汀类药物抑制胆固醇生物合成，并具有潜在的其他多种作用，称为多效性作用，是最广泛使用的降胆固醇药物。在这项研究中，我研究了染色对β-淀粉样蛋白和磷酸化tau蛋白产生的调节作用。最初建立稳定表达淀粉样前体蛋白（APP）或tau的SHSY-5 Y和Neuro 2a细胞用于进一步测定。当细胞与他汀类药物孵育时，全长APP和APP C-末端片段的水平升高。在高浓度他汀类药物作用下，Aβ42/40比值明显升高。总tau蛋白和磷酸化tau蛋白水平明显不受他汀类药物治疗的影响。这些结果表明，细胞渗透性他汀类药物对APP代谢有影响。

项目成果

Clinical and genetic characterizations of 16q-linked autosomal dominant spinocerebellar ataxia (AD-SCA) and frequency analysis of AD-SCA in the Japanese population

• DOI: 10.1002/mds.21443
• 发表时间: 2007-04-30
• 期刊: MOVEMENT DISORDERS
• 影响因子: 8.6
• 作者: Nozaki, Hiroaki;Ikeuchi, Takeshi;Onodera, Osamu
• 通讯作者: Onodera, Osamu

Mutational analysis of early-onset familial dementia: role of PSEN1 mutations and MAPT R406W mutation

早发家族性痴呆的突变分析：PSEN1突变和MAPT R406W突变的作用

• 发表时间: 2008
• 期刊: Dementia and Geriatric Cognitive Disorders (In press)
• 作者: Ikeuchi;et. al.
• 通讯作者: et. al.

A Presenilin-1 Mutant, AT440, Enhances Accumulation of Phosphorylated a-Synuclein in Culture Cells and Autopsied Brain.

Presenilin-1 突变体 AT440 可增强培养细胞和尸检大脑中磷酸化 a-突触核蛋白的积累。

• 发表时间: 2007
• 作者: Kaneko;H;et. al.
• 通讯作者: et. al.

PS1変異とα-synuclein蓄積

PS1 突变和 α-突触核蛋白积累

• 发表时间: 2006
• 期刊: Dementia Japan 20
• 作者: 池内 健;石川 厚
• 通讯作者: 石川 厚

Dentatorubral-pallidoluysian atrophy (DRPい): clinical and genetic features, and neuroimaging.

齿状红核-苍白球路易体萎缩（DRP）：临床和遗传特征以及神经影像学。

• 作者: Ikeuchi;et. al.
• 通讯作者: et. al.