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的和不断增加的社会经济负担。 包括阿尔茨海默病在内的与年龄相关的痴呆症是一些最大的未得到满足的医学 美国人口老龄化面临的挑战。到目前为止，对这些疾病的临床干预已经 尽管在开发新疗法方面做出了很大努力，但影响非常小。这一景观表明，我们是 仍然缺乏关于这些疾病的根本原因和特定细胞 导致疾病发展的脆弱性。我们认为，这些疾病的一个关键因素可能是 与局部突触新陈代谢有关。从新陈代谢的角度来看，大脑非常脆弱：严重 低血糖会导致明显和严重的神经问题，包括精神错乱和昏迷。此外，由于 我们变老(而变老是所有这些痛苦中最相关的)我们输送燃料的效率 到组织(包括大脑)，并将这种燃料转化为有用的生化货币，高能 中间的三磷酸腺苷(ATP)，两者都能降解。尽管这些神经退行性疾病 最终导致神经元死亡被认为是由突触引起的更早的症状问题 功能障碍。我的实验室最近发现，神经末梢代表了 大脑的新陈代谢脆弱性：他们消耗大量的三磷酸腺苷，但几乎没有储存快速可用的高能量 因此必须在局部合成三磷酸腺苷以维持功能。我们还发现，突触 依靠几种机制来上调对突触功能至关重要的三磷酸腺苷。此外，我们 发现静息神经末梢消耗大量的三磷酸腺苷来维持突触小泡质子 梯度，但这种能量负荷可能因神经递质类型而异。我们建议测试一下 神经退行性疾病有很强的局部代谢成分的假说 神经退行性疾病的遗传驱动因素特别影响局部代谢平衡，并对 确定这是否可能是疾病驱动的突触损伤的驱动因素。尽管某些神经退行性变 疾病最初表现为其他明显的症状(例如运动障碍)，随着时间的推移 大多数患者最常转化为痴呆症。在这里，使用量化方法，我们将 确定代谢脆弱神经元群体中的神经末梢依赖糖酵解还是依赖糖酵解 氧化磷酸化以支持功能，检查是否维持囊泡质子梯度较大 神经末梢的能量负荷(Aim1)，决定了疾病突变是否与 线粒体的完整性特别影响三磷酸腺苷(AIM2)的平衡，并决定是否有许多其他已知的 疾病相关突变通过改变局部的ATP生产平衡而增加新陈代谢易感性 与这一关键神经元群体中的消耗(Aim3)进行比较。从中学到的教训和见解 然后，研究应该被证明是有价值的，可以为更大类别的痴呆症的病理提供信息。

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.