Center for Neuroscience and Cell Biology, Laboratory of Physiology- Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal.
Curr Alzheimer Res. 2013 May 1;10(4):406-19. doi: 10.2174/1567205011310040006.
This study aimed to show that the rat model of sporadic Alzheimer's disease (sAD) generated by the intracerebroventricular (icv) injection of a sub-diabetogenic dose of streptozotocin (icvSTZ) is characterized by brain mitochondrial abnormalities. Three-month-old male Wistar rats were investigated 5 weeks after a single bilateral icv injection of STZ (3 mg/ Kg) or vehicle. icvSTZ administration induced a decrease in brain weight and cognitive decline, without affecting blood glucose levels. icvSTZ administration also resulted in a significant increase in hippocampal amyloid beta peptide 1-42 (Aβ(1-42)) levels as well as in cortical and hippocampal hyperphosphorylated tau protein levels. Brain mitochondria from icvSTZ rats revealed deficits in their function, as shown by a decrease in mitochondrial transmembrane potential, repolarization level, ATP content, respiratory state 3, respiratory control ratio and ADP/O index and an increase in lag phase of repolarization. Mitochondria from icvSTZ rats also displayed a decrease in pyruvate and α-ketoglutarate dehydrogenases and cytochrome c oxidase activities and an increase in the susceptibility to calcium-induced mitochondrial permeability transition. An increase in hydrogen peroxide and lipid peroxidation levels and a reduction in glutathione content were also observed in mitochondria from icvSTZ rats. These results demonstrate that the insulin-resistant brain state that characterizes this rat model of sAD is accompanied by the occurrence of mitochondrial abnormalities reinforcing the validity of this animal model to study sAD pathogenesis and potential therapies.
本研究旨在表明，通过侧脑室（icv）注射亚致糖尿病剂量链脲佐菌素（icvSTZ）生成的散发性阿尔茨海默病（sAD）大鼠模型存在脑线粒体异常。研究了 3 月龄雄性 Wistar 大鼠在单侧双侧 icv 注射 STZ（3mg / Kg）或载体 5 周后的情况。 icvSTZ 给药导致脑重量下降和认知能力下降，而不影响血糖水平。 icvSTZ 给药还导致海马淀粉样β肽 1-42（Aβ（1-42））水平以及皮质和海马过度磷酸化tau 蛋白水平显著升高。 icvSTZ 大鼠的脑线粒体功能出现缺陷，表现为线粒体跨膜电位、复极化水平、ATP 含量、呼吸状态 3、呼吸控制比和 ADP/O 指数降低，复极化滞后期延长。 icvSTZ 大鼠的线粒体还显示出丙酮酸和α-酮戊二酸脱氢酶和细胞色素 c 氧化酶活性降低，以及对钙诱导的线粒体通透性转换的敏感性增加。 icvSTZ 大鼠的线粒体还观察到过氧化氢和脂质过氧化水平增加，谷胱甘肽含量减少。这些结果表明，这种 sAD 大鼠模型所特有的胰岛素抵抗脑状态伴随着线粒体异常的发生，这增强了该动物模型研究 sAD 发病机制和潜在治疗方法的有效性。
