The distinct roles of AMPK in neurons and astrocytes following stroke

描述（由申请人提供）：amp活化蛋白激酶（AMPK）正在成为大脑能量平衡的关键传感器。在外周，AMPK急性调节细胞代谢，慢性调节基因表达，减少能量储存，增加能量产生（糖酵解、脂肪酸氧化和糖原利用）。我们已经证明AMPK在大脑中高度表达，并在缺血等能量剥夺状态下迅速激活。然而，AMPK激活在中风中的后果可能是复杂的，因为两种主要类型的脑细胞，神经元和星形胶质细胞，在代谢方面是不同的。与外周组织不同，神经元缺乏通过糖酵解产生ATP的关键酶，糖酵解是缺血时激活的主要ATP生成途径。此外，神经元不能有效地氧化脂肪酸，也没有糖原储存。因此可以预测，在严重缺血时通过上调神经元AMPK激活分解代谢过程会导致代谢衰竭和酸中毒。相反，星形胶质细胞可以进行糖酵解，氧化脂肪酸形成酮，并储存一些糖原，为缺血神经元提供能量供应。另外，令人信服的证据表明，星形胶质细胞通过ATP的产生和释放，可以通过减少兴奋毒性、降低钙内流和减少小胶质细胞介导的炎症来保护神经元。星形细胞AMPK的激活可能会减轻脑缺血损伤。这凸显了检验这种影响的重要性

DESCRIPTION (provided by applicant): AMP-activated protein kinase (AMPK) is emerging as a key sensor of brain energy balance. In the periphery, AMPK acutely regulates cellular metabolism and chronically regulates gene expression, reducing energy storage and increasing energy production (glycolysis, fatty acid oxidation and glycogen utilization). We have demonstrated that AMPK is highly expressed in brain and is rapidly activated in energy deprived states such as ischemia. However, the consequences of AMPK activation in stroke may be complex as the two major types of brain cells, neurons and astrocytes, are metabolically distinct. Unlike peripheral tissues, neurons are lacking the key enzymes to produce ATP via glycolysis, the major ATP-generating pathway activated during ischemia. In addition, neurons do not oxidize fatty acids efficiently, and have no glycogen stores. Therefore it could be predicted that activating catabolic processes by up-regulation of neuronal AMPK during severe ischemia would propagate metabolic failure and acidosis. In contrast, astrocytes can perform glycolysis, oxidize fatty acids to form ketones, and store some glycogen providing an energy supply for ischemic neurons. Compelling evidence additionally demonstrates that through ATP production and release, astrocytes may protect neurons by reducing excitotoxicity, lowering calcium influx and decreasing microglia mediated inflammation. Activation of astrocytic AMPK will likely reduce cerebral ischemic injury. This highlights the importance of examining the effect of loss of AMPK selectively in astrocytes or neurons following stroke. We have developed mice that are deficient in the catalytic isoforms of AMPK in either neurons or astrocytes. We found that mice deficient in AMPK in astrocytes had worse functional recovery after stroke; interestingly we also observed increased hemorrhagic transformation in these astrocytic KO mice after stroke. The overall goal of this proposal is to first characterize stroke outcome on cel specific AMPK manipulation and secondly determine the metabolic response to such manipulation. Selectively targeting AMPK signaling, a fundamental metabolic pathway, will not only provide us with a better scientific understanding of basic neuronal and astrocytic energy dynamics, but will also allow us to identify cellular specific targets for future clinical development. PUBLIC HEALTH RELEVANCE: Stroke is the third leading cause of death in the U.S., and the most common cause of disability. AMPK is a key energy metabolic sensor, but its role in neurons and astrocytes may differ and produce significant and distinct effects on stroke outcome. In this application, we will initiate a focused investigation on the consequences of cell selective AMPK deletion an attempt to develop novel and specific treatments for stroke.