Entorhinal Cortex dysfunction can be rescued by inhibition of microglial RAGE in an Alzheimer's disease mouse model.
Entorhinal Cortex dysfunction can be rescued by inhibition of microglial RAGE in an Alzheimer's disease mouse model.
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DOI：
10.1038/srep42370
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发表时间：
2017-02-13
影响因子：
4.6
通讯作者：
Origlia N
中科院分区：
文献类型：
--
作者：
Criscuolo C;Fontebasso V;Middei S;Stazi M;Ammassari-Teule M;Yan SS;Origlia N
内嗅皮层(EC)被认为与阿尔茨海默病(AD)的早期阶段有关。特别是，神经元功能障碍在EC-海马区网络中的扩散已被提出。我们研究了携带表达人Aβ的人突变淀粉样前体蛋白的AD小鼠模型中内皮细胞功能障碍的时间进程。我们发现，在mhAPP小鼠中，可塑性损害首先在EC浅层观察到，并随着时间的推移而进一步影响。在2月龄mhAPP小鼠EC切片的第II层水平连接中，LTP出现选择性损伤，而在神经变性后期(6月龄)，LTP的基础突触传递和LTD也受到影响。因此，mhAPP小鼠早期的突触缺陷与EC依赖的联想记忆任务中的选择性损害有关。在mhAPP小鼠中引入针对小胶质细胞(DNMSR)的缺乏RAGE信号的显性-负性RAGE形式，防止了突触和行为缺陷，减少了应激相关激酶(p38MAPK和JNK)的激活。我们的结果支持EC参与淀粉样蛋白依赖型神经变性过程中突触和行为缺陷的发展和进展，并表明在β丰富的环境中激活小胶质细胞RAGE是EC脆弱性的原因。
The Entorhinal cortex (EC) has been implicated in the early stages of Alzheimer’s disease (AD). In particular, spreading of neuronal dysfunction within the EC-Hippocampal network has been suggested. We have investigated the time course of EC dysfunction in the AD mouse model carrying human mutation of amyloid precursor protein (mhAPP) expressing human Aβ. We found that in mhAPP mice plasticity impairment is first observed in EC superficial layer and further affected with time. A selective impairment of LTP was observed in layer II horizontal connections of EC slices from 2 month old mhAPP mice, whereas at later stage of neurodegeneration (6 month) basal synaptic transmission and LTD were also affected. Accordingly, early synaptic deficit in the mhAPP mice were associated with a selective impairment in EC-dependent associative memory tasks. The introduction of the dominant-negative form of RAGE lacking RAGE signalling targeted to microglia (DNMSR) in mhAPP mice prevented synaptic and behavioural deficit, reducing the activation of stress related kinases (p38MAPK and JNK). Our results support the involvement of the EC in the development and progression of the synaptic and behavioural deficit during amyloid-dependent neurodegeneration and demonstrate that microglial RAGE activation in presence of Aβ-enriched environment contributes to the EC vulnerability.