Lamotrigine attenuates deficits in synaptic plasticity and accumulation of amyloid plaques in APP/PS1 transgenic mice
Lamotrigine attenuates deficits in synaptic plasticity and accumulation of amyloid plaques in APP/PS1 transgenic mice
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拉莫三嗪减轻 APP/PS1 转基因小鼠的突触可塑性缺陷和淀粉样斑块的积累
DOI：
10.1016/j.neurobiolaging.2014.06.009
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发表时间：
2014-12-01
影响因子：
4.2
通讯作者：
Xu, Ru-Xiang
中科院分区：
文献类型：
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作者：
Zhang, Mao-Ying;Zheng, Chuan-Yi;Xu, Ru-Xiang
多动及其代偿机制可能导致阿尔茨海默病（AD）的突触和认知缺陷。用左乙拉西坦（LEV）（一种用于治疗癫痫的钠通道阻滞剂）阻断神经网络的过度兴奋，可预防人淀粉样前体蛋白（APP）转基因小鼠的突触和认知缺陷。本研究为抗癫痫药物在AD治疗中的应用带来了新的前景。我们发现，拉莫三嗪（LTG），一种广谱AED，长期治疗，抑制异常的棘波活动，防止丢失的棘，突触素免疫反应，和神经元，从而衰减突触可塑性和学习和记忆的APP和早老素1（PS1）小鼠，表达人类突变APP和PS1的赤字。与未能减少淀粉样蛋白β生成的LEV相比，长期LTG治疗减少了β分泌酶对APP的切割，从而减少了APP和PS1小鼠脑中淀粉样蛋白斑块的数量和大小。此外，脑源性神经营养生长因子（BDNF）和神经生长因子（NGF）的水平在APP和PS 1小鼠的大脑中的慢性LTG治疗增强。因此，这些观察结果表明LTG通过多种机制减轻AD病理，包括调节异常网络活性、减少淀粉样蛋白β的产生以及上调BDNF和NGF。(C)2014 Elsevier Inc. All rights reserved.
Hyperactivity and its compensatory mechanisms may causally contribute to synaptic and cognitive deficits in Alzheimer's disease (AD). Blocking the overexcitation of the neural network, with levetiracetam (LEV), a sodium channel blocker applied in the treatment of epilepsy, prevented synaptic and cognitive deficits in human amyloid precursor protein (APP) transgenic mice. This study has brought the potential use of antiepileptic drugs (AEDs) in AD therapy. We showed that the chronic treatment with lamotrigine (LTG), a broad-spectrum AED, suppressed abnormal spike activity, prevented the loss of spines, synaptophysin immunoreactivity, and neurons, and thus attenuated the deficits in synaptic plasticity and learning and memory in APP and presenilin 1 (PS1) mice, which express human mutant APP and PS1. In contrast with LEV, which failed to reduce the generation of amyloid beta, the chronic LTG treatment reduced the cleavage of APP by beta-secretase and thus the numbers and the size of amyloid plaques in the brains of APP and PS1 mice. Moreover, the levels of brain-derived neurotrophic growth factor (BDNF) and nerve growth factor (NGF) were enhanced in the brains of APP and PS1 mice by the chronic LTG treatment. Therefore, these observations demonstrate that LTG attenuates AD pathology through multiple mechanisms, including modulation of abnormal network activity, reduction of the generation of amyloid beta and upregulation of BDNF and NGF. (C) 2014 Elsevier Inc. All rights reserved.