Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model
Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model
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DOI：
10.1073/pnas.1121081109
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发表时间：
2012-10-16
影响因子：
11.1
通讯作者：
Mucke, Lennart
中科院分区：
文献类型：
--
作者：
Sanchez, Pascal E.;Zhu, Lei;Mucke, Lennart
鉴于阿尔茨海默病（AD）的患病率不断上升，迫切需要新的策略来预防，阻止和逆转这种疾病。在AD患者和增加发展AD风险的条件下观察到脑网络活动的扰动，表明异常的网络活动可能有助于AD相关的认知能力下降。人淀粉样前体蛋白（hAPP）转基因小鼠模拟AD的关键方面，包括脑中淀粉样β肽水平的病理性升高、异常神经网络活动、海马回路的重塑、突触缺陷和行为异常。这些改变是否在因果链中联系仍然未知。为了探讨hAPP/淀粉样蛋白β诱导的异常网络活动是否有助于突触和认知缺陷，我们用不同的抗癫痫药物治疗hAPP小鼠。在测试的药物中，只有左乙拉西坦（LEV）有效地减少了脑电图检测到的异常尖峰活动。LEV长期治疗还逆转了hAPP小鼠的海马重塑、行为异常、突触功能障碍以及学习和记忆缺陷。我们的研究结果支持这一假设，即异常的网络活动导致hAPP小鼠的突触和认知缺陷。LEV也可能有助于改善患有AD或有AD风险的人的相关异常。
In light of the rising prevalence of Alzheimer's disease (AD), new strategies to prevent, halt, and reverse this condition are needed urgently. Perturbations of brain network activity are observed in AD patients and in conditions that increase the risk of developing AD, suggesting that aberrant network activity might contribute to AD-related cognitive decline. Human amyloid precursor protein (hAPP) transgenic mice simulate key aspects of AD, including pathologically elevated levels of amyloid-beta peptides in brain, aberrant neural network activity, remodeling of hippocampal circuits, synaptic deficits, and behavioral abnormalities. Whether these alterations are linked in a causal chain remains unknown. To explore whether hAPP/amyloid-beta-induced aberrant network activity contributes to synaptic and cognitive deficits, we treated hAPP mice with different antiepileptic drugs. Among the drugs tested, only levetiracetam (LEV) effectively reduced abnormal spike activity detected by electroencephalography. Chronic treatment with LEV also reversed hippocampal remodeling, behavioral abnormalities, synaptic dysfunction, and deficits in learning and memory in hAPP mice. Our findings support the hypothesis that aberrant network activity contributes causally to synaptic and cognitive deficits in hAPP mice. LEV might also help ameliorate related abnormalities in people who have or are at risk for AD.