Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, USA.
J Alzheimers Dis. 2010;20 Suppl 2:S535-50. doi: 10.3233/JAD-2010-100342.
Mitochondrial dysfunction is observed in Alzheimer's disease (AD) brain, and the amyloid-beta (Abeta) peptide is known to induce mitochondrial dysfunction. The relative degree of mitochondrial dysfunction in different regions of the brain in AD is not completely understood. Moreover, the relationship between levels of synaptic mitochondrial Abeta and mitochondrial dysfunction has not been clearly established. Therefore synaptic and nonsynaptic mitochondria were isolated from the hippocampus, cortex, striatum, and amygdala of 12 month AbetaPPsw and AbetaPP+PS1 mouse models of AD as well as nontransgenic mice. Mitochondrial respiratory rates, reactive oxygen species production, membrane potential, and cytochrome c oxidase activity were measured. Hippocampal and cortical mitochondria showed the highest levels of mitochondrial dysfunction, while striatal mitochondria were moderately affected, and amygdalar mitochondria were minimally affected. Mitochondria from AbetaPP/PS1 brain regions were more impaired than those from AbetaPP mice. Mitochondrial Abeta levels nearly mirrored the extent of mitochondrial dysfunction. Synaptic mitochondria were more impaired than nonsynaptic mitochondria in the AD mouse models. The AbetaPP/PS1 mice showed more impairment in the cognitive interference task of working memory than the AbetaPP mice. The association between mitochondrial Abeta levels and mitochondrial dysfunction in mouse models of AD supports a primary role for mitochondrial Abeta in AD pathology. Moreover, the degree of cognitive impairment in AD transgenic mice can be linked to the extent of synaptic mitochondrial dysfunction and mitochondrial Abeta levels, suggesting that a mitochondrial Abeta-induced signaling cascade may contribute to cognitive impairment. Therapeutics that target this cascade could be beneficial in the treatment of AD.
线粒体功能障碍在阿尔茨海默病（AD）脑中观察到，并且已知淀粉样β（Abeta）肽可诱导线粒体功能障碍。AD 大脑不同区域中线粒体功能障碍的相对程度尚不完全清楚。此外，突触线粒体 Abeta 的水平与线粒体功能障碍之间的关系尚未明确确立。因此，从 12 个月 AbetaPPsw 和 AbetaPP+PS1 AD 转基因小鼠模型以及非转基因小鼠的海马体、皮层、纹状体和杏仁核中分离出突触和非突触线粒体。测量线粒体呼吸速率、活性氧产生、膜电位和细胞色素 c 氧化酶活性。海马体和皮质线粒体显示出最高水平的线粒体功能障碍，而纹状体线粒体受到中度影响，杏仁核线粒体受到最小影响。AbetaPP/PS1 脑区的线粒体比 AbetaPP 小鼠的线粒体受损更严重。AD 小鼠模型中的突触线粒体比非突触线粒体受损更严重。AbetaPP/PS1 小鼠在工作记忆的认知干扰任务中的表现比 AbetaPP 小鼠更差。AD 转基因小鼠中线粒体 Abeta 水平与线粒体功能障碍之间的关联支持线粒体 Abeta 在 AD 病理学中的主要作用。此外，AD 转基因小鼠认知障碍的程度与突触线粒体功能障碍和线粒体 Abeta 水平相关，表明线粒体 Abeta 诱导的信号级联可能导致认知障碍。针对该级联的治疗方法可能对 AD 的治疗有益。
