Metabolic Vulnerability of Synapses in Neurodegenerative Disease

摘要 与年龄相关的神经退行性疾病给社会带来了巨大且日益增加的社会经济负担。 包括阿尔茨海默病在内的与痴呆症有关的痴呆症代表了一些最大的未满足的医疗需求， 美国人口老龄化所面临的挑战。迄今为止，针对这些疾病的临床干预措施已经 尽管在开发新疗法方面做出了重大努力，但影响非常有限。这幅景象表明我们 仍然缺乏关于这些疾病的根本原因和特定细胞的基本信息， 导致疾病进展的脆弱性。我们认为，这些疾病的一个关键因素可能 与局部突触代谢有关。从新陈代谢的角度来看，大脑是非常脆弱的：严重的 低血糖导致明显和严重的神经问题，包括谵妄和昏迷。此外如 我们老化（老化是所有这些痛苦中最强烈的相关性），我们可以提供燃料的效率 到组织（包括大脑），并将这种燃料转化为有用的生化货币，即高能量 中间体三磷酸腺苷（ATP），两者都降解。虽然这些神经退行性疾病 最终导致神经元死亡，但据认为，更早的症状性问题出现于突触 功能障碍我的实验室最近发现，神经末梢代表了一个可能的位点， 大脑的代谢脆弱性：它们消耗大量的ATP，但几乎不储存快速可用的高能量 因此必须局部合成ATP以维持功能。我们还发现突触 依赖于几种机制来上调突触功能所必需的ATP。另外我们 发现静息神经末梢消耗大量ATP来维持突触囊泡质子 梯度，但这种能量负担可能因神经递质类型而异。我们建议测试 假设神经退行性疾病有很强的局部代谢成分， 神经退行性疾病的遗传驱动因素特别影响局部代谢平衡， 确定这是否可能是疾病驱动的突触损伤的驱动因素。虽然某些神经退行性疾病 疾病最初出现其他明显症状（例如运动障碍），随着时间的推移， 在大多数患者中最常转变为痴呆。在这里，使用定量方法，我们将 确定代谢脆弱神经元群体中的神经末梢如何依赖糖酵解与糖酵解 氧化磷酸化以支持功能，检查是否维持囊泡质子梯度， 神经末梢的能量负担（Aim 1），确定是否与疾病相关的突变 线粒体完整性特别影响ATP（AIM 2）的平衡，并确定是否有一些其他已知的 疾病相关突变通过改变ATP产生的局部平衡而增加代谢脆弱性 与此关键神经元群体中的消耗相比（Aim3）。从中吸取的教训和见解 因此，研究应证明在为更大类别的痴呆症提供病理学信息方面具有价值。

Abstract Age-related neurodegenerative diseases place a substantial and increasing socioeconomic burden on society. Age-related dementias including Alzheimer’s disease represent some of the greatest unmet medical challenges facing the aging population in the US. To date clinical interventions for these diseases have had very modest impact despite major efforts to develop new therapeutics. This landscape suggests that we are still missing fundamental information regarding the root cause of these diseases and the specific cellular vulnerabilities that lead to disease progression. We propose that a critical element of theses disease may relate to local synaptic metabolism. The brain is highly vulnerable from a metabolic point of view: severe hypoglycemia results in overt and severe neurological problems including delirium and coma. Furthermore, as we age (and aging is the strongest correlate of all these afflictions) the efficiency with which we can deliver fuel to tissues (including the brain) and convert this fuel into the useful biochemical currency, the high-energy intermediate adenosine tri-phosphate (ATP), both degrade. Although these neurodegenerative disorders ultimately lead to neuronal death it is thought that much earlier symptomatic problems arise from synaptic dysfunction. My laboratory recently discovered that nerve terminals represent one of the likely loci of the brain’s metabolic vulnerability: they consume large amounts of ATP but store little rapidly usable high-energy molecules and must therefore locally synthesize ATP to maintain function. We also discovered that synapses relay on several mechanisms to upregulate ATP that are essential for synapse function. Additionally, we discovered resting nerve terminals consume large amounts of ATP to maintain the synaptic vesicles proton gradient but that this energy burden likely varies across neurotransmitter type. We propose to test the hypothesis that neurodegenerative diseases have a strong local metabolic component by examining how genetic drivers of neurodegenerative disease specifically impact the local metabolic balance and do to determine if this might be a driver of disease-driven synapse impairment. Although certain neurodegenerative diseases disease initially present with other overt symptoms (for example movement disorders) over time they most frequently convert to dementias in the majority of patients. Here using quantitative approaches we will determine how nerve terminals in a metabolically vulnerable neuron population rely upon glycolysis versus oxidative phosphorylation to support function, examine if maintaining the vesicle proton gradient places a large energetic burden on the nerve terminals (Aim1), determine if the disease mutations associated with mitochondrial integrity specifically impact the balance of ATP (AIM2) and determine if a number of other known disease associated mutations increase metabolic vulnerability by altering the local balance of ATP production versus consumption in this critical neuron population (Aim3). The lessons and insights learned from these studies should then prove valuable in informing the pathology of a larger class of dementias.