Su J H, Deng G, Cotman C W
Institute for Brain Aging and Dementia, University of California at Irvine 92697-4540, USA.
Neurobiol Dis. 1997;4(5):365-75. doi: 10.1006/nbdi.1997.0164.
Neurofibrillary tangles and dystrophic neurites appear to develop in a highly characteristic spatial and temporal sequence in AD. In order to examine the nature of the cellular progression we have studied the trisynaptic entorhinal, dentate gyrus, CA3/4 circuit, using an antibody to hyperphosphorylated tau which is a biochemical marker for tangle formation. In early AD cases, we found numerous ATB-stained boutons in the outer molecular layer of the dentate gyrus, the termination field of neurons from the entorhinal cortex. These AT8-stained boutons co-labeled with synaptophysin, indicating that they represent synaptic boutons in an early state of degeneration. Since the labeled boutons were apposed to or clustered around dendrites or soma that lacked or had less intense staining for AT8 or PHF-1, it appeared that presynaptic events preceded postsynaptic neurofibrillary tangle formation. Furthermore, as a function of disease progression, the pattern of degeneration moved through the circuit. In this progression tau, which is normally localized to axons, becomes redistributed into dendrites and hyperphosphorylated. These observations support the hypothesis that the presynaptic terminal changes may promote the formation of initial neurofibrillary pathology in the postsynaptic neurons via anterograde transneuronal mechanisms and that this initiates a breakdown of routing and sorting mechanisms for the cytoskeletal protein tau.
在阿尔茨海默病（AD）中，神经原纤维缠结和营养不良性神经突似乎以高度特征性的空间和时间顺序发展。为了研究细胞进展的本质，我们使用针对过度磷酸化tau的抗体（tau是缠结形成的生化标志物），对三突触内嗅、齿状回、CA3/4回路进行了研究。在早期AD病例中，我们在齿状回的外分子层发现了大量AT8染色的终扣，这里是内嗅皮质神经元的终末场。这些AT8染色的终扣与突触素共标记，表明它们代表处于早期退化状态的突触终扣。由于标记的终扣与对AT8或PHF-1缺乏染色或染色较弱的树突或胞体相邻或聚集在一起，似乎突触前事件先于突触后神经原纤维缠结的形成。此外，随着疾病进展，退化模式在回路中移动。在这个过程中，通常定位于轴突的tau会重新分布到树突中并过度磷酸化。这些观察结果支持这样的假设，即突触前终末变化可能通过顺行跨神经元机制促进突触后神经元中初始神经原纤维病理的形成，并且这会引发细胞骨架蛋白tau的运输和分选机制的破坏。
