Role of the steroid hormone ADIOL in learning and memory, aging, and neurodegeneration

项目摘要/摘要 目前缺乏改善认知衰退的治疗方法，这种衰退的特点是 神经退行性疾病，如阿尔茨海默病(AD)和AD相关痴呆(ADRD)。中的缺陷 学习和记忆也伴随着衰老。我们一直在研究犬尿酸KYNA，一种色氨酸 作为线虫新陈代谢、衰老以及学习和记忆的纽带而衍生的代谢物。的确有 来自包括线虫和小鼠在内的多种物种的令人信服的证据表明，KYNA的减少改善了 当这种神经调节代谢物增加时，学习和记忆会产生有害的影响。在这两种情况下，C. 秀丽和小鼠的KYNA随着年龄的增长而积累。Kyna的积累也伴随着人类的衰老和 神经退行性疾病包括AD和ADRDS。使用基因操作，我们之前展示了 降低KYNA水平显著改善了老年线虫和线虫的学习和记忆能力。 优雅的神经退行性变模型。这些改善是由于KYNA对活动的特定影响 表达N-甲基-D-天冬氨酸受体(NMDAR)的神经元，学习和 跨越系统发展史的记忆。这些发现促使我们寻找分子机制和药理学 还原KYNA的试剂。我们鉴定了雄酮-5-烯-3β，17-β-二醇(ADIOL)，一种C19类固醇激素 线虫体内KYNA的有效减少剂和学习能力的增强剂。我们已经证明了 ADIOL的作用依赖于NHR-91，一种既有序列又有功能的转录因子 与哺乳动物雌激素受体β、ERβ同源。这些发现耐人寻味的原因有两个：(I) ADIOL在哺乳动物中的存在早已被认识到，但这种类固醇的生理功能 激素了解极少，(Ii)有令人信服的证据表明，ERβ在 哺乳动物有许多有益的效果，包括改善学习和记忆，但潜在的 机制尚不清楚。我们假设ADIOL作为内源性配体激活内质网β样蛋白 核激素受体，这反过来导致KYNA减少，以促进学习和记忆。我们的 具体目标是严格确定ADIOL在衰老和C。 优雅的神经退行性变模型，设计生物化学策略从 研究NHR-91作为ADIOL和KYNA之间的机制链接的作用，并探索三个 关于ADIOL的生理作用的假说，包括它在衰老中的作用，作为一种连接机制 营养感官途径通过KYNA学习和记忆，并作为一种连接发育的机制 对学习和记忆机制的生殖能力。这项研究使用了线虫分子 遗传学、成像、行为分析以及代谢物的生化测量。

PROJECT SUMMARY/ABSTRACT There is currently a paucity of therapeutic approaches for ameliorating cognitive declines that characterize neurodegenerative disorders such as Alzheimer's Disease (AD) and AD related dementias (ADRDs). Defects in learning and memory also accompany aging. We have been investigating kynurenic acid, KYNA, a tryptophan derived metabolite, as a nexus in metabolism, aging, and learning and memory in C. elegans. There is compelling evidence from multiple species including C. elegans and mice that reductions in KYNA improve learning and memory while increases in this neuromodulatory metabolite have detrimental effects. In both C. elegans and mice KYNA accumulates with age. KYNA accumulation also accompanies human aging and neurodegenerative disorders including AD and ADRDs. Using genetic manipulations, we previously showed that reducing KYNA levels substantially improves learning and memory in aged C. elegans as well as in C. elegans models of neurodegeneration. These improvements are due to specific effects of KYNA on the activity of neurons that express N-methyl D-aspartate receptors (NMDARs), fundamental regulators of learning and memory across phylogeny. These findings prompted us to seek molecular mechanisms and pharmacological reagents for reducing KYNA. We have identified androst-5-ene-3β,17β-diol (ADIOL), a C19 steroid hormone, as a potent reducer of KYNA and enhancer of learning capacity in C. elegans. We have demonstrated that the effects of ADIOL are dependent on an NHR-91, a transcription factor with both sequence and functional homology to mammalian estrogen receptor β, ERβ. These findings are intriguing for two key reasons: (i) The existence of ADIOL has long been recognized in mammals but the physiological functions of this steroid hormone are extremely poorly understood, (ii) There is compelling evidence that activation of ERβ in mammals has numerous beneficial effects including improved learning and memory but the underlying mechanisms are unknown. We hypothesize that ADIOL serves as an endogenous ligand to activate an ERβ-like nuclear hormone receptor, which in turn causes reductions in KYNA to promote learning and memory. Our specific aims are to rigorously establish the role of ADIOL in learning and memory during aging and in C. elegans models of neurodegeneration, devise biochemical strategies for quantitating this steroid hormone from C. elegans, investigate the role of nhr-91 as a mechanistic link between ADIOL and KYNA, and explore three hypotheses pertaining to the physiological roles of ADIOL including its role in aging, as a mechanism that links nutrient sensory pathways to learning and memory via KYNA, and as a mechanism that links development of reproductive capacity to mechanisms of learning and memory. This investigation employs C. elegans molecular genetics, imaging, behavioral assays, as well as biochemical measurements of metabolites.