Interdepartmental Program of Neuroscience, University of California, Los Angeles, CA, USA.
Lab Invest. 2010 May;90(5):774-86. doi: 10.1038/labinvest.2010.6. Epub 2010 Feb 15.
Over half of multiple sclerosis (MS) patients experience cognitive deficits, including learning and memory dysfunction, and the mechanisms underlying these deficits remain poorly understood. Neuronal injury and synaptic loss have been shown to occur within the hippocampus in other neurodegenerative disease models, and these pathologies have been correlated with cognitive impairment. Whether hippocampal abnormalities occur in MS models is unknown. Using experimental autoimmune encephalomyelitis (EAE), we evaluated hippocampal neurodegeneration and inflammation during disease. Hippocampal pathology began early in EAE disease course, and included decreases in CA1 pyramidal layer volume, loss of inhibitory interneurons and increased cell death of neurons and glia. It is interesting to note that these effects occurred in the presence of chronic microglial activation, with a relative paucity of infiltrating blood-borne immune cells. Widespread diffuse demyelination occurred in the hippocampus, but there was no significant decrease in axonal density. Furthermore, there was a significant reduction in pre-synaptic puncta and synaptic protein expression within the hippocampus, as well as impaired performance on a hippocampal-dependent spatial learning task. Our results demonstrate that neurodegenerative changes occur in the hippocampus during autoimmune-mediated demyelinating disease. This work establishes a preclinical model for assessing treatments targeted toward preventing hippocampal neuropathology and dysfunction in MS.
超过一半的多发性硬化症 (MS) 患者存在认知缺陷，包括学习和记忆功能障碍，而这些缺陷的潜在机制仍知之甚少。在其他神经退行性疾病模型中，已经观察到海马体中的神经元损伤和突触丢失，并且这些病理学与认知障碍相关。MS 模型中是否存在海马体异常尚不清楚。我们使用实验性自身免疫性脑脊髓炎 (EAE) 评估了疾病期间海马体的神经退行性变和炎症。海马体病理学在 EAE 病程早期开始，包括 CA1 锥体层体积减少、抑制性中间神经元丢失以及神经元和神经胶质细胞死亡增加。有趣的是，这些影响发生在慢性小胶质细胞激活的情况下，浸润性血液免疫细胞相对较少。海马体中广泛发生弥漫性脱髓鞘，但轴突密度没有明显下降。此外，海马体中突触前小体和突触蛋白表达显著减少，以及在海马体依赖的空间学习任务中表现受损。我们的研究结果表明，在自身免疫介导的脱髓鞘疾病中，海马体发生了神经退行性变化。这项工作建立了一个临床前模型，用于评估针对预防 MS 中海马体神经病理学和功能障碍的治疗方法。
