Early glial activation, synaptic changes and axonal pathology in the thalamocortical system of Niemann-Pick type C1 mice.
Early glial activation, synaptic changes and axonal pathology in the thalamocortical system of Niemann-Pick type C1 mice.
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DOI：
10.1016/j.nbd.2011.12.027
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发表时间：
2012-03
影响因子：
6.1
通讯作者：
Cooper, Jonathan D.
中科院分区：
文献类型：
--
作者：
Pressey, Sarah N. R.;Smith, David A.;Wong, Andrew M. S.;Platt, Frances M.;Cooper, Jonathan D.
关键词：
C型尼曼-匹克病（NPC）是一种遗传性溶酶体贮积病，其特征是胆固醇和鞘糖脂蓄积。NPC患者患有进行性神经退行性表型，表现为运动功能障碍、智力迟钝和认知能力下降。为了研究NPC中神经病理损伤的发生和进展，我们系统地检查了NPC 1小鼠模型（Npc 1 −/−小鼠）在疾病过程不同阶段的CNS。这揭示了Npc 1 −/−小鼠神经病理学的特定空间和时间模式，强调了感觉丘脑通路特别容易受到Npc 1丢失的影响，导致Npc 1 −/−小鼠神经退行性变。检查星形细胞增多和小胶质细胞活化的标志物显示，在疾病早期丘脑中有特别明显的反应性胶质细胞增生，随后在以后的年龄也发生在相互连接的皮质层中。我们对事件精确分期的研究表明，Npc 1 −/−小鼠脑区之间神经胶质和神经元之间的关系各不相同，这表明引起神经胶质反应的线索可能在脑区之间存在差异。此外，突触前标记物的聚集在白色物质束和丘脑中是明显的，并且可能在轴突球体内形成。我们的数据提供了一个新的视角，揭示了一些发生在神经元损失之前和同时发生的事件，并强调这些事件以通路依赖的方式发生。Npc 1 −/−小鼠模型中定义的C型尼曼匹克神经病理学分期。⑶探讨了萎缩、神经元丢失和胶质细胞活化之间的关系。病理学在相互连接的感觉丘脑皮质通路中最为明显。►神经胶质激活先于神经元损失的开始。突触前标记物重排，白色物质萎缩。
Niemann–Pick disease type C (NPC) is an inherited lysosomal storage disease characterised by accumulation of cholesterol and glycosphingolipids. NPC patients suffer a progressive neurodegenerative phenotype presenting with motor dysfunction, mental retardation and cognitive decline. To examine the onset and progression of neuropathological insults in NPC we have systematically examined the CNS of a mouse model of NPC1 (Npc1−/− mice) at different stages of the disease course. This revealed a specific spatial and temporal pattern of neuropathology in Npc1−/− mice, highlighting that sensory thalamic pathways are particularly vulnerable to loss of NPC1 resulting in neurodegeneration in Npc1−/− mice. Examination of markers of astrocytosis and microglial activation revealed a particularly pronounced reactive gliosis in the thalamus early in the disease, which subsequently also occurred in interconnected cortical laminae at later ages. Our examination of the precise staging of events demonstrate that the relationship between glia and neurons varies between brain regions in Npc1−/− mice, suggesting that the cues causing glial reactivity may differ between brain regions. In addition, aggregations of pre-synaptic markers are apparent in white matter tracts and the thalamus and are likely to be formed within axonal spheroids. Our data provide a new perspective, revealing a number of events that occur prior to and alongside neuron loss and highlighting that these occur in a pathway dependent manner. ► Staging of neuropathology defined in Npc1−/− mouse model of Niemann–pick type C. ► The relationship between atrophy, neuron loss and glial activation are explored. ► Pathology was most pronounced in interconnecting sensory thalamocortical pathways. ► Glial activation precedes the onset of neuron loss. ► Pre-synaptic markers are rearranged and white matter is atrophied.
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影响因子：
4.1
作者：
DeLong, Mahlon;Wichmann, Thomas
通讯作者：
Wichmann, Thomas
影响因子：
12.7
作者：
Bradl M;Lassmann H
通讯作者：
Lassmann H
DOI：
10.1083/jcb.58.1.135
发表时间：
1973-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kadota K;Kadota T
通讯作者：
Kadota T
影响因子：
2
作者：
Gundersen, HJG;Jensen, EBV;Nielsen, J
通讯作者：
Nielsen, J
DOI：
10.2174/1566524023362375
发表时间：
2002-08-01
期刊：
Current Molecular Medicine (Hilversum)
影响因子：
--
作者：
Garver, William S.;Heidenreich, Randall A.
通讯作者：
Heidenreich, Randall A.