Macauley Shannon L, Stanley Molly, Caesar Emily E, Yamada Steven A, Raichle Marcus E, Perez Ronaldo, Mahan Thomas E, Sutphen Courtney L, Holtzman David M
J Clin Invest. 2015 Jun;125(6):2463-7. doi: 10.1172/JCI79742. Epub 2015 May 4.
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-β (Aβ), glucose, and lactate within the hippocampal interstitial fluid (ISF). In a murine model of AD, induction of acute hyperglycemia in young animals increased ISF Aβ production and ISF lactate, which serves as a marker of neuronal activity. These effects were exacerbated in aged AD mice with marked Aβ 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 Aβ 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 Aβ levels.
流行病学研究表明，2型糖尿病（T2DM）患者以及血糖在非糖尿病情况下升高的个体患痴呆症的风险增加，尤其是患阿尔茨海默病（AD）所致的痴呆症。这些观察结果表明，异常的葡萄糖代谢可能在AD发病机制的某些方面发挥作用，促使我们在小鼠模型中研究异常葡萄糖代谢、T2DM和AD之间的联系。在这里，我们结合了两种技术——葡萄糖钳夹技术和体内微透析技术，作为在清醒、自由活动的小鼠中动态调节血糖水平的一种手段，同时测量海马间质液（ISF）中淀粉样β蛋白（Aβ）、葡萄糖和乳酸的实时变化。在AD小鼠模型中，幼龄动物急性高血糖的诱导增加了ISF中Aβ的产生和ISF乳酸水平，乳酸是神经元活动的标志物。在具有明显Aβ斑块病理改变的老龄AD小鼠中，这些效应更加明显。内向整流型ATP敏感性钾（K(ATP)）通道介导了对葡萄糖水平升高的反应，因为对海马中K(ATP)通道的药理学操作改变了ISF中Aβ水平和神经元活动。综上所述，这些结果表明，K(ATP)通道激活通过将代谢与神经元活动及ISF中Aβ水平相耦合，介导了海马神经元对高血糖的反应。
