Severely dystrophic axons at amyloid plaques remain continuous and connected to viable cell bodies
Severely dystrophic axons at amyloid plaques remain continuous and connected to viable cell bodies
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DOI：
10.1093/brain/awn312
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发表时间：
2009-02-01
期刊：
影响因子：
14.5
通讯作者：
Coleman, Michael P.
中科院分区：
文献类型：
--
作者：
Adalbert, Robert;Nogradi, Antal;Coleman, Michael P.
在阿尔茨海默病中，突触丧失先于细胞死亡，但轴突变性与这些事件相关的时间以及因果关系仍不清楚。淀粉样斑块附近的轴突变得严重营养不良，以致轴突中断，导致功能永久性丧失、突触广泛丧失，并可能导致细胞死亡。然而，目前尚不清楚轴突是否真正在斑块处被中断以及细胞体是否无法支撑其轴突和树突。我们纵向追踪 TgCRND8 小鼠轴突穿过营养不良区域、远端和近端。相应的神经元不仅存活下来，而且形态保持不变，表明轴突损伤信号传导不存在或无法对其做出反应。无论营养不良程度如何，轴突在斑块区域外都保持连续且最初形态正常，反映了代谢活跃的细胞体和持续轴突运输的支持。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密切相关，表明局部功能受损。因此，我们排除了长程退化轴突或树突作为该模型中早期突触丧失的主要因素，从而提高了在轴突高度营养不良后持续数月甚至数年的单个神经元功能拯救的治疗窗口的前景。我们认为，多灶性病理学在人类疾病中发挥着重要作用，它导致局部的、可能可恢复的突触损失转变为神经元过程及其细胞体的永久性损失。
Synapse loss precedes cell death in Alzheimers 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.