Department of Neuroscience, Scripps Research Institute Florida, Jupiter, Florida, 33458, USA.
Mol Neurobiol. 2021 Jan;58(1):143-155. doi: 10.1007/s12035-020-02107-w. Epub 2020 Sep 9.
Many different cellular systems and molecular processes become compromised in Alzheimer's disease (AD) including proteostasis, autophagy, inflammatory responses, synapse and neuronal circuitry, and mitochondrial function. We focused in this study on mitochondrial dysfunction owing to the toxic neuronal environment produced by expression of Aβ42, and its relationship to other pathologies found in AD including increased neuronal apoptosis, plaque deposition, and memory impairment. Using super-resolution microscopy, we have assayed mitochondrial status in the three distinct neuronal compartments (somatic, dendritic, axonal) of mushroom body neurons of Drosophila expressing Aβ42. The mushroom body neurons comprise a major center for olfactory memory formation in insects. We employed calcium imaging to measure mitochondrial function, immunohistochemical and staining techniques to measure apoptosis and plaque formation, and olfactory classical conditioning to measure learning. We found that mitochondria become fragmented at a very early age along with decreased function measured by mitochondrial calcium entry. Increased apoptosis and plaque deposition also occur early, yet interestingly, a learning impairment was found only after a much longer period of time-10 days, which is a large fraction of the fly's lifespan. This is similar to the pronounced delay between cellular pathologies and the emergence of a memory dysfunction in humans. Our studies are consistent with the model that mitochondrial dysfunction and/or other cellular pathologies emerge at an early age and lead to much later learning impairments. The results obtained further develop this Drosophila model as a useful in vivo system for probing the mechanisms by which Aβ42 produces mitochondrial and other cellular toxicities that produce memory dysfunction.
许多不同的细胞系统和分子过程在阿尔茨海默病（AD）中受到损害，包括蛋白质稳态、自噬、炎症反应、突触和神经元回路以及线粒体功能。由于 Aβ42 表达产生的有毒神经元环境，以及与 AD 中发现的其他病理学的关系，包括增加的神经元凋亡、斑块沉积和记忆损伤，我们在本研究中专注于线粒体功能障碍。使用超分辨率显微镜，我们检测了表达 Aβ42 的果蝇蘑菇体神经元的三个不同神经元区室（体、树突、轴突）中的线粒体状态。蘑菇体神经元是昆虫嗅觉记忆形成的主要中心。我们采用钙成像来测量线粒体功能，免疫组织化学和染色技术来测量凋亡和斑块形成，以及嗅觉经典条件反射来测量学习。我们发现，线粒体在非常早期就出现碎片化，同时伴随着线粒体钙进入功能下降。凋亡和斑块沉积也很早就发生了，但有趣的是，只有在很长一段时间后——10 天后才发现学习障碍，这是果蝇寿命的很大一部分。这类似于细胞病理学和人类记忆功能障碍之间出现的明显延迟。我们的研究与线粒体功能障碍和/或其他细胞病理学在早期出现并导致学习障碍延迟很久的模型一致。这些结果进一步发展了这种果蝇模型，作为一种有用的体内系统，用于研究 Aβ42 产生线粒体和其他细胞毒性导致记忆功能障碍的机制。
