Synaptic loss in Alzheimer’s disease (AD) is strongly correlated with cognitive impairment. Accumulating evidence indicates that amyloid pathology leads to synaptic degeneration and mitochondrial damage in AD. However, it remains unclear whether synapses and presynaptic mitochondria are differentially affected in various cortical regions of the AD brain at the ultrastructural level. Using serial block-face scanning electron microscopy, we assessed synaptic structures in the medial prefrontal cortex (mPFC) and primary visual cortex (V1) of the 5xFAD mouse model of AD. At 6 months of age, 5xFAD mice exhibited significantly elevated levels of amyloid deposition in layer 2/3 of the mPFC but not V1. Accordingly, three-dimensional reconstruction of synaptic connectivity revealed a significant reduction in excitatory synaptic density in layer 2 of the mPFC, but not V1, of male transgenic mice. Notably, the density of synapses lacking presynaptic mitochondria was selectively decreased in the mPFC of 5xFAD mice, with no change in the density of mitochondria-containing synapses. Further classification of spines into shape categories confirmed a preferential loss of thin spines whose presynaptic boutons were largely devoid of mitochondria in the 5xFAD mPFC. Furthermore, the number of mitochondria per bouton in spared mitochondria-containing boutons was reduced in the mPFC, but not V1, of 5xFAD mice. Collectively, these results highlight region-specific vulnerability of cortical synapses to amyloid deposition and suggest that the presence of presynaptic mitochondria may affect synaptic degeneration in AD.

中文翻译：

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在5xFAD小鼠模型中缺乏突触前线粒体的皮质突触的选择性区域性丢失。

阿尔茨海默氏病（AD）的突触丧失与认知障碍密切相关。越来越多的证据表明，淀粉样蛋白病理导致AD中的突触变性和线粒体损伤。然而，目前尚不清楚突触和突触前线粒体是否在超微结构水平上在AD大脑的各个皮质区域中受到不同的影响。使用串行块面扫描电子显微镜，我们评估了AD的5xFAD小鼠模型的内侧前额叶皮层（mPFC）和初级视觉皮层（V1）中的突触结构。在6个月大时，5xFAD小鼠在mPFC的2/3层中显示出明显升高的淀粉样蛋白沉积水平，但在V1中则没有。因此，突触连接性的三维重建显示，雄性转基因小鼠的mPFC的第2层（而不是V1）的兴奋性突触密度显着降低。值得注意的是，缺乏突触前线粒体的突触的密度在5xFAD小鼠的mPFC中选择性降低，而含线粒体的突触的密度没有变化。在5xFAD mPFC中，进一步将棘突分类为形状类别证实了其细突棘的优先损失，这些细突触前突的突突在很大程度上没有线粒体。此外，在5xFAD小鼠的mPFC中，每只胸腺中含有线粒体的线粒体中的线粒体数目减少了，但V1却没有减少。总的来说，