Advanced glycation endproducts (AGEs) as metabolic by-products that mediate neurodegeneration.

项目总结/摘要 衰老和慢性高血糖症会导致多种代谢和生化紊乱，包括 一系列高活性α-二羰基化合物（α-DC，例如，甲基乙二醛（MGO）。α-树突状细胞 是不可避免的副产物，主要是厌氧糖酵解，不加选择地与蛋白质，脂质， 和DNA产生一组异质的分子，称为晚期糖基化终产物（AGEs）。一 大量证据表明，葡萄糖代谢加速和糖尿病与神经退行性疾病有关， 老年痴呆症（AD）。我们假设葡萄糖代谢的有毒副产物， 导致AGEs形成的原因解释了高血糖和糖尿病导致AD风险增加的原因。支持 这种AGEs在血清和AGE交联蛋白质聚集体已与增强 AD中的神经变性。然而，AGEs很难建模，因为它们需要数年时间才能在人体内积累， 它们引起细胞损伤的机制仍有待阐明。为了克服这一差距，我们 建立C。elegans（蠕虫）模型，显著积累α-DCs和AGEs，表现出几个年龄- 相关的病理，如对触摸的超敏反应，神经元损伤，瘫痪和早期死亡，所有 在成年后的三周内。此外，我们还观察到，直接给予合成的 丙酮醛衍生的AGEs可直接引起神经毒性。此外，我们还观察到，一个C。 一种过度表达tau蛋白前聚集形式的线虫模型，该模型与阿尔茨海默氏症有关 疾病，对饮食中的葡萄糖或AGEs敏感。在本提案中，我们将检验假设 葡萄糖和脂质代谢途径的变化，特别是随着年龄的增长，影响MGO和相关的 AGEs从而导致与AD相关的神经变性。我们还将通过以下方式确定机制 这些AGEs影响代谢功能障碍并导致AD中的神经变性。 在目标1中，我们将探讨AGEs对正常衰老和衰老过程中神经退行性变的影响的因果关系。 使用合成衍生AGEs的阿尔茨海默病模型。我们还将研究与年龄相关的 糖代谢的改变影响MGO和AGEs的水平并增强神经退行性变 在AD模型中。在目标2中，我们将确定脂质代谢和AGEs产生之间的关系。 我们将从遗传学和生物学的角度操纵脂肪酸氧化途径， 通过调节AGEs来调节正常衰老和AD模型中的神经变性。在目标3中， 建议确定AGEs介导其毒性导致脂肪酸抑制的机制 氧化和神经变性。我们将确定AGE结合蛋白和治疗靶点， 与年龄有关的神经变性。这些研究将确定几个遗传和药理学靶点， 改善AGEs，减缓AD神经退行性变的进展。

PROJECT SUMMARY/ ABSTRACT Aging and chronic hyperglycemia results in several metabolic and biochemical perturbations including elevation of a series of highly reactive α-dicarbonyl compounds (α-DCs, e.g., Methylglyoxal(MGO). α-DCs are unavoidable byproducts largely of anaerobic glycolysis which react indiscriminately with proteins, lipids, and DNA to yield a heterogeneous group of molecules called advanced glycation end products (AGEs). A large body of evidence has linked accelerated glucose metabolism and diabetes to neurodegenerative diseases like Alzheimer's disease (AD). We hypothesize that toxic byproducts of glucose metabolism that result in the formation of AGEs explain the enhanced risk of AD due to hyperglycemia and diabetes. In support of this AGEs in serum and AGE crosslinking in protein aggregates have been associated with enhanced neurodegeneration in AD. However, AGEs are hard to model as they take years to accumulate in humans and the mechanism by which they cause cellular damage remains to be elucidated. To overcome this gap, we have established C. elegans (worm) models that significantly accumulate α-DCs and AGEs, exhibiting several age- related pathologies, such as hypersensitivity to touch, neuronal damage, paralysis, and early mortality, all within three weeks of adulthood. In addition, we have observed that direct administration of synthetic methylglyoxal derived AGEs can directly cause neurotoxicity. Furthermore, we have observed that a C. elegans model overexpressing the pro-aggregating form of tau, that has been implicated in Alzheimer's disease, is sensitive to feeding either glucose or AGEs in the diet. In this proposal, we will test the hypothesis that changes in glucose and lipid metabolism pathways, especially with age, influence MGO and associated AGEs thereby causing neurodegeneration associated with AD. We will also determine the mechanisms by which AGEs influence metabolic dysfunction and contribute to neurodegeneration in AD. In Aim 1 we will explore a causal role for the effects of AGEs on neurodegeneration in normal aging and in Alzheimer's disease models using synthetically derived AGEs. We will also examine the role of age-associated changes in glucose metabolism in influencing the levels of MGO and AGEs and enhancing neurodegeneration in models of AD. In Aim 2 we will determine the relationship between lipid metabolism and production of AGEs. We will genetically and pharmacologically manipulate fatty acid oxidation pathways to examine their influence on modulating neurodegeneration in normal aging and AD models through modulation of AGEs. In Aim 3 we propose to identify the mechanisms by which AGEs mediate their toxicity leading to inhibition of fatty acid oxidation and neurodegeneration. We will identify AGE-binding proteins and therapeutic targets to modulate AGE-related neurodegeneration. These studies will identify several genetic and pharmacological targets to ameliorate AGEs and slow down the progression of neurodegeneration in AD.