Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer's disease
Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer's disease
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DOI：
10.1073/pnas.1206171109
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发表时间：
2012-05-29
影响因子：
11.1
通讯作者：
Konnerth, Arthur
中科院分区：
文献类型：
--
作者：
Busche, Marc Aurel;Chen, Xiaowei;Konnerth, Arthur
阿尔茨海默病（AD）的特征是中枢神经元进行性功能障碍。近期的实验证据表明，在大脑皮层中，除了一部分神经元沉默外，在富含β - 淀粉样蛋白（Aβ）斑块的区域其他神经元过度活跃。然而，神经元沉默和过度活跃哪个先出现，以及原发性神经元功能障碍可能的潜在机制仍然未知。在此我们利用双光子Ca2 +成像技术在体内研究AD小鼠模型中海马CA1神经元的活动模式。我们发现老年小鼠带有斑块的CA1区域的神经元活动发生了深刻改变。沉默神经元和过度活跃神经元的比例都显著增加，这与之前在大脑皮层中发现的情况一样。值得注意的是，在年轻小鼠的海马体中，我们观察到在斑块形成之前过度活跃的神经元就已经选择性增加，这表明可溶性Aβ可能是这种损伤的原因。事实上，我们发现用γ - 分泌酶抑制剂LY - 411575进行急性治疗可降低可溶性Aβ水平并挽救神经元功能障碍。此外，我们证明直接应用可溶性Aβ可在野生型小鼠中诱导神经元过度活跃。因此，我们的研究确定海马体过度活跃是AD转基因小鼠中一种非常早期的功能损伤，并提供直接证据表明可溶性Aβ对海马体过度活跃至关重要。
Alzheimer's disease (AD) is characterized by a progressive dysfunction of central neurons. Recent experimental evidence indicates that in the cortex, in addition to the silencing of a fraction of neurons, other neurons are hyperactive in amyloid-beta (A beta) plaque-enriched regions. However, it has remained unknown what comes first, neuronal silencing or hyperactivity, and what mechanisms might underlie the primary neuronal dysfunction. Here we examine the activity patterns of hippocampal CA1 neurons in a mouse model of AD in vivo using two-photon Ca2+ imaging. We found that neuronal activity in the plaque-bearing CA1 region of older mice is profoundly altered. There was a marked increase in the fractions of both silent and hyperactive neurons, as previously also found in the cortex. Remarkably, in the hippocampus of young mice, we observed a selective increase in hyperactive neurons already before the formation of plaques, suggesting that soluble species of A beta may underlie this impairment. Indeed, we found that acute treatment with the gamma-secretase inhibitor LY-411575 reduces soluble A beta levels and rescues the neuronal dysfunction. Furthermore, we demonstrate that direct application of soluble A beta can induce neuronal hyperactivity in wild-type mice. Thus, our study identifies hippocampal hyperactivity as a very early functional impairment in AD transgenic mice and provides direct evidence that soluble A beta is crucial for hippocampal hyperactivity.