Sensory network dysfunction, behavioral impairments, and their reversibility in an Alzheimer's β-amyloidosis mouse model.
Sensory network dysfunction, behavioral impairments, and their reversibility in an Alzheimer's β-amyloidosis mouse model.
复制标题
感觉网络功能障碍，行为障碍及其在阿尔茨海默氏症的β-淀粉样变性小鼠模型中的可逆性。
DOI：
10.1523/jneurosci.2085-11.2011
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发表时间：
2011-11-02
期刊：
影响因子：
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通讯作者：
Wilson DA
中科院分区：
文献类型：
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作者：
Wesson DW;Borkowski AH;Landreth GE;Nixon RA;Levy E;Wilson DA
嗅觉系统对阿尔茨海默病（AD）具有独特的易感性，这为理解该疾病中突触功能障碍和病理进展的机制提供了一种典型的转化工具。利用β -淀粉样变的Tg2576小鼠模型，我们发现异常的、过度活跃的嗅觉网络活动在生命早期就开始了，此时还没有可检测到的行为损伤或类似的海马功能障碍，并且β -淀粉样蛋白（Aβ）沉积仅限于嗅球（OB）。梨状皮质（PCX）中气味诱发的过度活跃活动以及嗅球 - 梨状皮质功能连接性的增强出现在与嗅觉行为损伤同时发生的时间点。这种过度活跃的活动一直持续到晚年，此时网络转变为低反应状态。这种转变是依赖于Aβ的，因为使用肝X受体激动剂治疗以促进Aβ降解，可以挽救低反应状态和嗅觉行为。这些数据为阿尔茨海默病中嗅觉功能障碍的一种新的工作模型提供了证据，并且与其他近期的研究成果相辅相成，表明与疾病相关的网络功能障碍是高度动态的且具有区域特异性，但对认知和行为具有持久的影响。
The unique vulnerability of the olfactory system to Alzheimer’s disease (AD) provides a quintessential translational tool for understanding mechanisms of synaptic dysfunction and pathological progression in the disease. Using the Tg2576 mouse model of β-amyloidosis, we show aberrant, hyperactive olfactory network activity begins early in life, prior to detectable behavioral impairments or comparable hippocampal dysfunction and at a time when Aβ deposition is restricted to the olfactory bulb (OB). Hyperactive odor-evoked activity in the piriform cortex (PCX) and increased OB-PCX functional connectivity emerged at a time coinciding with olfactory behavior impairments. This hyperactive activity persisted until later-life when the network converted to a hyporesponsive state. This conversion was Aβ-dependent, as liver-x-receptor agonist treatment to promote Aβ degradation, rescued the hyporesponsive state and olfactory behavior. These data lend evidence to a novel working model of olfactory dysfunction in AD and, complimentary to other recent works, suggest that disease-relevant network dysfunction is highly dynamic and region specific, yet with lasting effects on cognition and behavior.