Adalbert Robert, Nogradi Antal, Babetto Elisabetta, Janeckova Lucie, Walker Simon A, Kerschensteiner Martin, Misgeld Thomas, Coleman Michael P
The Babraham Institute, Babraham Research Campus, Babraham, Cambridge, UK.
Brain. 2009 Feb;132(Pt 2):402-16. doi: 10.1093/brain/awn312. Epub 2008 Dec 5.
Synapse loss precedes cell death in Alzheimer's disease, but the timing of axon degeneration relative to these events, and the causal relationships remain unclear. Axons become so severely dystrophic near amyloid plaques that their interruption, causing permanent loss of function, extensive synapse loss, and potentially cell death appears imminent. However, it remains unclear whether axons are truly interrupted at plaques and whether cell bodies fail to support their axons and dendrites. We traced TgCRND8 mouse axons longitudinally through, distal to, and proximal from dystrophic regions. The corresponding neurons not only survived but remained morphologically unaltered, indicating absence of axonal damage signalling or a failure to respond to it. Axons, no matter how dystrophic, remained continuous and initially morphologically normal outside the plaque region, reflecting support by metabolically active cell bodies and continued axonal transport. Immunochemical and ultrastructural studies showed dystrophic axons were tightly associated with disruption of presynaptic transmission machinery, suggesting local functional impairment. Thus, we rule out long-range degeneration axons or dendrites as major contributors to early synapse loss in this model, raising the prospect of a therapeutic window for functional rescue of individual neurons lasting months or even years after their axons become highly dystrophic. We propose that multi-focal pathology has an important role in the human disease in bringing about the switch from local, and potentially recoverable, synapse loss into permanent loss of neuronal processes and eventually their cell bodies.
在阿尔茨海默病中，突触丧失先于细胞死亡，但轴突退变相对于这些事件的时间以及因果关系仍不清楚。在淀粉样斑块附近，轴突会出现严重的营养不良，以至于其中断，导致功能永久丧失、广泛的突触丧失以及潜在的细胞死亡似乎即将发生。然而，目前尚不清楚轴突在斑块处是否真的中断，以及细胞体是否无法支持其轴突和树突。我们纵向追踪了TgCRND8小鼠轴突穿过、远离和靠近营养不良区域的情况。相应的神经元不仅存活下来，而且形态上保持不变，这表明不存在轴突损伤信号或对其无反应。轴突无论营养不良程度如何，在斑块区域外仍保持连续且最初形态正常，这反映了代谢活跃的细胞体的支持以及轴突运输的持续进行。免疫化学和超微结构研究表明，营养不良的轴突与突触前传递机制的破坏紧密相关，提示局部功能受损。因此，在该模型中，我们排除了长距离轴突或树突退变是早期突触丧失的主要原因，这为在轴突变得高度营养不良数月甚至数年之后对单个神经元进行功能挽救提供了治疗窗口的可能性。我们提出，多灶性病理在人类疾病中具有重要作用，它导致了从局部的、可能可恢复的突触丧失转变为神经元突起最终其细胞体的永久性丧失。
