Fundamental research about the ketone body therapy for Alzheimer's disearse.

酮体治疗阿尔茨海默病的基础研究。

• 批准号: 11670625
• 负责人: NAKASHIMA Kenji
• 金额: $ 2.3万
• 依托单位: Tottori University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670625/
• 关键词: Ketone Body; Amyloid βpeptide; Primary Hippocampal culture; Alzheimer's model; Energy crisis; マイクロアイランド培養法; 初代海馬神経培養

We have created the Amyloid beta protein toxicity model using rat primary hippocampal culture. Hippocampal cells are taken from 18 day fetal SD rats, which were cultured with absolute serum free medium. We have succeeded low density culture more that 7 days, with well neurites grouth and without increasing glial cells. Exposure of 5μ amyloicl s 1-42 peptide (Aβl-42) decreased cell number and neurite number and length in comparison to control. Addition of ketones to cells exposed to Aβ1-42 doubled the survived cell number and increased cell size and neurite outgrowth compared with cells exposed to Aβ1-42. Even we have developed the septum culture as well as hippocampal culture, the immunostaining with cholinergic neurons is unstable to have a quantitative data at this point.It is known that Aβ1-42 is increased up to 6 fold in brains from patients with Alzheimer's disease and that Aβ1-42 inactivates the pyruvate dehydrogenase (PDH) complex in septal neurons by activating the protein kinase. D-(-)-β-hydroxybutyrate (DBHB) is a normal substrate in brain, with provides Acetyl CoA to TCA cycle directly with bypassing PDH complex, and also produce the reducing agent NADH.It was thought that DBHB could rescue hippocampal neurons from the toxicity of Aβ1-42 with mechanism mentioned above. These data, which resulted that ketone bodies provide a neuroprotective effect against with increased levels of Aβ1-42, suggest that ketone body could be a potential candidate for use in the treatment of Alzheimer's disease and other neurological diseases associated with energy crisis.

我们使用大鼠原代海马培养物建立了淀粉样β蛋白毒性模型。海马细胞取自18天胎龄SD大鼠，用无血清培养基培养。低密度培养7天以上，神经突起生长良好，神经胶质细胞不增加。与对照组相比，5μ淀粉样s 1-42肽（Aβ 1 -42）暴露减少了细胞数量和神经突数量和长度。与暴露于Aβ1-42的细胞相比，向暴露于A β 1 - 42的细胞中添加酮可使存活细胞数量增加一倍，并增加细胞大小和神经突生长。即使我们已经开发了隔区培养和海马培养，胆碱能神经元的免疫染色仍不稳定，无法获得定量数据。已知Aβ1-42在阿尔茨海默病患者的脑中增加至6倍，并且Aβ1-42通过激活蛋白激酶使隔区神经元中的丙酮酸脱氢酶（PDH）复合物失活。D-（-）-β-羟基丁酸酯（DBHB）是脑内的正常底物，通过绕过PDH复合物直接为TCA循环提供乙酰辅酶A，并产生还原剂NADH，故认为DBHB可通过上述机制拯救海马神经元免受Aβ1-42的毒性。这些数据表明，酮体对Aβ1-42水平升高具有神经保护作用，表明酮体可能是治疗阿尔茨海默病和其他与能量危机相关的神经系统疾病的潜在候选药物。

项目成果

Kashiwaya, Y.: "D-β-Hydroxybutyrate Protects Neurons in Models of Alzheimer's and Parkinson's Disease"Proc.Nat.Acad.Sci.of the USA. Vol.97. 5440-5444 (2000)

Kashiwaya, Y.：“D-β-羟基丁酸保护阿尔茨海默病和帕金森病模型中的神经元”Proc.Nat.Acad.Sci.of the USA 第 97 卷（2000 年）。