Early-Onset Network Hyperexcitability in Presymptomatic Alzheimer's Disease Transgenic Mice Is Suppressed by Passive Immunization with Anti-Human APP/Aβ Antibody and by mGluR5 Blockade.
Early-Onset Network Hyperexcitability in Presymptomatic Alzheimer's Disease Transgenic Mice Is Suppressed by Passive Immunization with Anti-Human APP/Aβ Antibody and by mGluR5 Blockade.
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DOI：
10.3389/fnagi.2017.00071
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发表时间：
2017
影响因子：
4.8
通讯作者：
Iqbal K
中科院分区：
文献类型：
--
作者：
Kazim SF;Chuang SC;Zhao W;Wong RK;Bianchi R;Iqbal K
皮质和海马网络过度兴奋似乎是阿尔茨海默病（AD）发病机制的早期事件，并可能导致记忆障碍。目前尚不清楚网络过度兴奋是否先于AD小鼠模型中的记忆障碍，以及潜在的细胞机制是什么。因此，我们在携带突变的人Aβ前体蛋白（APP）、tau和早老素1（PS1）基因的家族性AD三重转基因小鼠模型（3xTg-AD小鼠）中评价了约3周龄时[淀粉样蛋白β（Aβ）斑块沉积、神经病理学和认知障碍之前]的癫痫发作易感性和海马网络过度兴奋性。与野生型（WT）对照相比，在更高比例的3xTg-AD小鼠中引起听源性癫痫发作。通过抗人APP/Aβ抗体（6 E10）被动免疫或通过选择性拮抗剂2-甲基-6-（苯乙炔基）吡啶盐酸盐（MPEP）阻断代谢型谷氨酸受体5（mGluR 5）来减弱3xTg-AD小鼠的癫痫易感性。在体外海马切片中，用GABAA受体拮抗剂荷包牡丹碱抑制突触抑制，在来自3xTg-AD小鼠的大多数切片中，在CA 3神经元网络中诱导延长的癫痫样放电（持续时间>1.5 s）。相反，在WT切片的CA 3区应用荷包牡丹碱后，仅观察到短的癫痫样（持续时间<1.5 s）发作间期样放电。与盐水处理的3xTg-AD小鼠相比，6 E10免疫的小鼠海马CA 3区中的发作样活性显著降低。MPEP可明显抑制3xTg-AD脑片的癫痫样放电。值得注意的是，癫痫样放电持续时间与海马CA 3区神经元内人（转基因）APP/Aβ表达呈正相关。我们的数据表明，在家族性AD小鼠模型中，癫痫易感性的超同步网络活动先于Aβ斑块病理学和记忆障碍。在3xTg-AD小鼠中，这种早发性网络过度兴奋可通过抗人APP/Aβ抗体被动免疫和mGluR 5阻断来抑制。
Cortical and hippocampal network hyperexcitability appears to be an early event in Alzheimer’s disease (AD) pathogenesis, and may contribute to memory impairment. It remains unclear if network hyperexcitability precedes memory impairment in mouse models of AD and what are the underlying cellular mechanisms. We thus evaluated seizure susceptibility and hippocampal network hyperexcitability at ~3 weeks of age [prior to amyloid beta (Aβ) plaque deposition, neurofibrillary pathology, and cognitive impairment] in a triple transgenic mouse model of familial AD (3xTg-AD mouse) that harbors mutated human Aβ precursor protein (APP), tau and presenilin 1 (PS1) genes. Audiogenic seizures were elicited in a higher proportion of 3xTg-AD mice compared with wild type (WT) controls. Seizure susceptibility in 3xTg-AD mice was attenuated either by passive immunization with anti-human APP/Aβ antibody (6E10) or by blockade of metabotropic glutamate receptor 5 (mGluR5) with the selective antagonist, 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP). In in vitro hippocampal slices, suppression of synaptic inhibition with the GABAA receptor antagonist, bicuculline, induced prolonged epileptiform (>1.5 s in duration) ictal-like discharges in the CA3 neuronal network in the majority of the slices from 3xTg-AD mice. In contrast, only short epileptiform (<1.5 s in duration) interictal-like discharges were observed following bicuculline application in the CA3 region of WT slices. The ictal-like activity in CA3 region of the hippocampus was significantly reduced in the 6E10-immunized compared to the saline-treated 3xTg-AD mice. MPEP acutely suppressed the ictal-like discharges in 3xTg-AD slices. Remarkably, epileptiform discharge duration positively correlated with intraneuronal human (transgenic) APP/Aβ expression in the CA3 region of the hippocampus. Our data suggest that in a mouse model of familial AD, hypersynchronous network activity underlying seizure susceptibility precedes Aβ plaque pathology and memory impairment. This early-onset network hyperexcitability can be suppressed by passive immunization with an anti-human APP/Aβ antibody and by mGluR5 blockade in 3xTg-AD mice.