BACKGROUND Approved drugs for Alzheimer's disease (AD) only have a symptomatic effects and do not intervene causally in the course of the disease. Olesoxime (TRO19622) has been tested in AD disease models characterized by improved amyloid precursor protein processing (AβPP) and mitochondrial dysfunction. METHODS Three months old Thy-1-AβPPSL (tg) and wild type mice (wt) received TRO19622 (100 mg/kg b.w.) in supplemented food pellets for 15 weeks (tg TRO19622). Mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) levels were determined in dissociated brain cells (DBC). Respiration was analyzed in mitochondria isolated from brain tissue. Citrate synthase (CS) activity and beta-amyloid peptide (Aβ1-40) levels were determined in brain tissue. Malondialdehyde (MDA) levels were determined as an indicator for lipid peroxidation. DBC and brain homogenates were additionally stressed with Rotenone and FeCl2, respectively. Mitochondrial respiration and Aβ1-40 levels were also determined in HEK-AβPPsw-cells. RESULTS Treatment of mice did not affect the body weight. TRO19622 was absorbed after oral treatment (plasma levels: 6,2 μg/ml). Mitochondrial respiration was significantly reduced in brains of tg-mice. Subsequently, DBC isolated from brains of tg-mice showed significantly lower MMP but not ATP levels. TRO19622 increased the activity of respiratory chain complexes and reversed complex IV (CIV) activity and MMP. Moreover, DBC isolated from brains of tg TRO19622 mice were protected from Rotenone induced inhibition of complex I activity. TRO19622 also increased the respiratory activity in HEKsw-cells. MDA basal levels were significantly higher in brain homogenates isolated from tg-mice. TRO19622 treatment had no effects on lipid peroxidation. TRO19622 increased cholesterol levels but did not change membrane fluidity of synaptosomal plasma and mitochondrial membranes isolated from brain of mice. TRO19622 significantly increased levels of Aβ1-40 in both, in brains of tg TRO19622 mice and in HEKsw cells. CONCLUSIONS TRO19622 improves mitochondrial dysfunction but enhances Aβ levels in disease models of AD. Further studies must evaluate whether TRO19622 offers benefits at the mitochondrial level despite the increased formation of Aβ, which could be harmful.

中文翻译：

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在阿耳茨海默氏病的临床前模型中，奥来辛肟可改善脑线粒体功能障碍并提高Aβ水平。

背景技术批准的用于阿尔茨海默氏病（AD）的药物仅具有症状作用，并且在疾病过程中无因果关系。Olesoxime（TRO19622）已在AD疾病模型中进行了测试，其特征在于改善的淀粉样前体蛋白加工（AβPP）和线粒体功能障碍。方法3个月大的Thy-1-AβPPSL（tg）和野生型小鼠（wt）在补充食物颗粒中接受TRO19622（100 mg / kg体重），持续15周（tg TRO19622）。在分离的脑细胞（DBC）中测定线粒体膜电位（MMP）和三磷酸腺苷（ATP）水平。分析了从脑组织分离的线粒体中的呼吸。测定脑组织中的柠檬酸合酶（CS）活性和β-淀粉样肽（Aβ1-40）水平。测定丙二醛（MDA）水平作为脂质过氧化的指标。分别用鱼藤酮和FeCl2对DBC和脑匀浆施加压力。还测定了HEK-AβPPsw细胞的线粒体呼吸和Aβ1-40水平。结果小鼠的治疗没有影响体重。口服治疗后，TRO19622被吸收（血浆水平：6.2微克/毫升）。tg-小鼠的大脑线粒体呼吸明显减少。随后，从tg-小鼠脑中分离出的DBC显示出MMP明显降低，但ATP水平却没有。TRO19622增加了呼吸链复合物的活性，并逆转了复合物IV（CIV）的活性和MMP。而且，从tg TRO19622小鼠的大脑中分离出的DBC受到了鱼藤酮诱导的复合物I活性的抑制作用的保护。TRO19622还增加了HEKsw细胞的呼吸活动。从tg小鼠中分离出的脑匀浆中的MDA基础水平明显更高。TRO19622处理对脂质过氧化没有影响。TRO19622增加了胆固醇水平，但没有改变从小鼠脑中分离的突触体血浆和线粒体膜的膜流动性。TRO19622在tg TRO19622小鼠的大脑和HEKsw细胞中均显着增加Aβ1-40的水平。结论TRO19622可改善线粒体功能障碍，但可增强AD疾病模型中的Aβ水平。进一步的研究必须评估TRO19622是否在线粒体水平上提供了益处，尽管Aβ的形成增加了，这可能是有害的。TRO19622增加了胆固醇水平，但没有改变从小鼠脑中分离的突触体血浆和线粒体膜的膜流动性。TRO19622在tg TRO19622小鼠的大脑和HEKsw细胞中均显着增加Aβ1-40的水平。结论TRO19622可改善线粒体功能障碍，但可增强AD疾病模型中的Aβ水平。进一步的研究必须评估TRO19622是否在线粒体水平上提供了益处，尽管Aβ的形成增加了，这可能是有害的。TRO19622增加了胆固醇水平，但没有改变从小鼠脑中分离的突触体血浆和线粒体膜的膜流动性。TRO19622在tg TRO19622小鼠的大脑和HEKsw细胞中均显着增加Aβ1-40的水平。结论TRO19622可改善线粒体功能障碍，但可增强AD疾病模型中的Aβ水平。进一步的研究必须评估TRO19622是否在线粒体水平上提供了益处，尽管Aβ的形成增加了，这可能是有害的。