Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo
Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo
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DOI：
10.1172/jci79742
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发表时间：
2015-06-01
影响因子：
15.9
通讯作者：
Holtzman, David M.
中科院分区：
文献类型：
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作者：
Macauley, Shannon L.;Stanley, Molly;Holtzman, David M.
流行病学研究表明，2型糖尿病(T2 DM)患者和血糖非糖尿病非依赖性升高的人患痴呆症的风险增加，特别是阿尔茨海默病(AD)引起的痴呆症。这些观察表明，糖代谢异常可能在AD发病的某些方面起作用，这导致我们在小鼠模型中研究糖代谢异常、T2 DM和AD之间的联系。在这里，我们结合了葡萄糖钳夹和体内微透析两种技术，作为一种动态调节清醒、自由活动小鼠血糖水平的方法，同时测量海马区间质液(ISF)中淀粉样β蛋白(Aβ)、葡萄糖和乳酸的实时变化。在AD的小鼠模型中，幼年动物急性高血糖的诱导增加了ISF Aβ的产生和ISF乳酸的产生，ISF乳酸是神经元活动的标志。这些影响在老年AD小鼠身上加剧，这些小鼠有明显的Aβ斑块病理。内向整流、ATP敏感的钾(K(ATP)通道)通道介导了对高血糖水平的反应，因为对海马K-ATP通道的药理学操作改变了ISF AP水平和神经元活动。综上所述，这些结果提示K-ATP通道激活通过耦合代谢、神经元活动和ISF Aβ水平来介导海马神经元对高血糖的反应。
Epidemiological studies show that patients with type 2 diabetes (T2DM) and individuals with a diabetes-independent elevation in blood glucose have an increased risk for developing dementia, specifically dementia due to Alzheimer's disease (AD). These observations suggest that abnormal glucose metabolism likely plays a role in some aspects of AD pathogenesis, leading us to investigate the link between aberrant glucose Metabolism, T2DM, and AD in murine models. Here, we combined two techniques glucose clamps and in vivo microdialysis as a means to dynamically modulate blood glucose levels in awake, freely moving mice while measuring real-time changes in amyloid-beta (A beta), glucose, and lactate within the hippocampal interstitial fluid (ISF). In a murine model of AD, induction of acute hyperglycemia in young animals increased ISF A beta production and ISF lactate, which serves as a marker of neuronal activity. These effects were exacerbated in aged AD mice with marked A beta plaque pathology. Inward rectifying, ATP-sensitive potassium (k(ATP)) channels mediated the response to elevated glucose levels, as pharmacological manipulation of K-ATP channels in the hippocampus altered both ISF Ap levels and neuronal activity. Taken together, these results suggest that K-ATP channel activation mediates the response of hippocampal neurons to hyperglycemia by coupling metabolism with neuronal activity and ISF A beta levels.