DeWitt D A, Silver J
Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Exp Neurol. 1996 Nov;142(1):103-10. doi: 10.1006/exnr.1996.0182.
Although neuronal pathology and synaptic loss are salient features of Alzheimer's disease (AD), the underlying mechanisms involved are unknown. Using double-immunolabeled preparations, we found that both the density and the total lengths of axons are decreased within the A(beta)-containing area of senile plaques (SP) in comparison with the adjacent neuropil. These observations suggest that axotomy is occurring in the vicinity of the SP which could account for the synaptic loss. Since A(beta) in solution has been shown to be neurotoxic in vitro, we tested whether intact SP cores isolated from AD brain were equally detrimental when presented to retinal ganglion neurons. Surprisingly, SPs did not appear to be toxic or even repulsive to neurons since they adhered well and elaborated axons which wrapped tightly around the SP core. In the presence of cortical astrocytes, however, neurons appeared to avoid SP cores. We found that astrocytes accumulate and deposit chondroitin sulfate proteoglycans (CSPGs) around SP cores in vitro in a pattern similar to that observed around SPs in Alzheimer's disease brain. Neuronal avoidance of astrocyte-conditioned SP cores could be due to the axon outgrowth inhibitory nature of CSPGs. These results suggest that astrocytic reaction to SPs, including increased CSPGs, may facilitate the decreased axon density and synaptic loss in AD brain. Moreover, the similarities between swollen axon endings following axotomy in trauma and the dystrophic neurites of the SP suggest that dystrophic neurites in AD may be exhibiting regenerative failure rather than aberrant sprouting.
尽管神经元病理学改变和突触丧失是阿尔茨海默病（AD）的显著特征，但其中涉及的潜在机制尚不清楚。通过双免疫标记制备，我们发现与相邻神经毡相比，老年斑（SP）含Aβ区域内轴突的密度和总长度均降低。这些观察结果表明，轴突切断发生在SP附近，这可能是突触丧失的原因。由于已证明溶液中的Aβ在体外具有神经毒性，我们测试了从AD脑中分离出的完整SP核心在作用于视网膜神经节神经元时是否同样有害。令人惊讶的是，SP对神经元似乎没有毒性，甚至没有排斥作用，因为它们能很好地黏附并形成紧密包裹在SP核心周围的轴突。然而，在存在皮质星形胶质细胞的情况下，神经元似乎会避开SP核心。我们发现，星形胶质细胞在体外以与AD病脑中围绕SP观察到的模式相似的方式在SP核心周围积累并沉积硫酸软骨素蛋白聚糖（CSPG）。神经元对星形胶质细胞条件化的SP核心的回避可能是由于CSPG具有抑制轴突生长的特性。这些结果表明，星形胶质细胞对SP的反应，包括CSPG增加，可能促进了AD病脑中轴突密度降低和突触丧失。此外，创伤中轴突切断后肿胀的轴突末梢与SP营养不良性神经突之间的相似性表明，AD中的营养不良性神经突可能表现出再生失败而非异常发芽。
