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

类固醇激素 ADIOL 在学习和记忆、衰老和神经退行性疾病中的作用

• 批准号: 10231523
• 负责人: Kaveh Ashrafi
• 金额: $ 174.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231523
• 关键词: Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animals; Behavioral Assay; Biochemical; Caenorhabditis elegans; Cells; Data; Defect; Disease; Enhancers; Enzymes; Estrogen Receptor beta; Gap Junctions; Generations; Genes; Genetic Transcription; Glycols; Goals; Head; High Pressure Liquid Chromatography; Homologous Gene; Hormonal; Hormones; Human; Image; Impaired cognition; Insulin; Interneurons; Investigation; Kynurenic Acid; Kynurenine; Learning; Ligands; Link; Longevity; Mammals; Measurement; Mediating; Mediator of activation protein; Memory; Metabolism; Methodology; Modeling; Molecular; Molecular Genetics; Mus; N-Methyl-D-Aspartate Receptors; Names; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear Hormone Receptors; Nutrient; PGRN gene; Pathway interactions; Peripheral; Pharmacology; Phylogeny; Physiological; Physiology; Play; Production; Proteins; Reagent; Role; Sensory; Signal Transduction; Steroids; Study models; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transgenic Animals; Tryptophan; Variant; Work; aged; base; experimental study; genetic manipulation; granulin; improved; neuromechanism; neuroregulation; novel; protein TDP-43; receptor; reconstitution; relating to nervous system; reproductive; reproductive development; sensor; steroid hormone; tandem mass spectrometry; tau Proteins; therapy development; transcription factor

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.

项目摘要/摘要 目前缺乏用于改善认知下降的治疗方法，其特征在于 神经退行性疾病，如阿尔茨海默病（AD）和AD相关痴呆（ADRD）。缺陷 学习和记忆也伴随着衰老。我们一直在研究犬尿烯酸，KYNA，色氨酸 衍生代谢物，作为代谢，衰老，学习和记忆的C。优雅的有 包括C.线虫和小鼠，KYNA的减少改善了 学习和记忆，而这种神经调节代谢物的增加具有有害作用。在两个C. 线虫和小鼠KYNA随着年龄的增长而积累。KYNA的积累也伴随着人类的衰老， 神经退行性疾病，包括AD和ADRD。通过基因操作，我们之前展示了 降低KYNA水平可以显著改善老年人的学习和记忆。elegans和C. elegans神经退化模型。这些改善是由于KYNA对活性的特定影响 神经元表达N-甲基D-天冬氨酸受体（NMDAR），学习和 记忆中的一切这些发现促使我们寻求分子机制和药理学 还原KYNA的试剂。我们已经鉴定了雄甾-5-烯-3 β，17 β-二醇（ADIOL），一种C19类固醇激素， 一个有效的减少KYNA和增强学习能力的C。优雅的我们已经证明， ADIOL的作用依赖于NHR-91，NHR-91是一种具有序列和功能的转录因子， 与哺乳动物雌激素受体β，ERβ同源。这些发现是耐人寻味的两个关键原因：（一） ADIOL的存在在哺乳动物中早已被认识到，但这种类固醇的生理功能 对激素了解非常少，（ii）有令人信服的证据表明， 哺乳动物具有许多有益的作用，包括改善学习和记忆，但潜在的 机制不明。我们假设ADIOL作为内源性配体激活ERβ样受体， 核激素受体，从而导致KYNA减少，以促进学习和记忆。我们 具体目标是严格确定ADIOL在衰老过程中的学习和记忆中以及在C. elegans模型的神经变性，设计生化策略定量这种类固醇激素， C. elegans，研究nhr-91作为ADIOL和KYNA之间的机制联系的作用，并探索三个 关于ADIOL生理作用的假设，包括其在衰老中的作用，作为一种机制， 通过KYNA的营养感觉途径学习和记忆，并作为一种机制， 学习和记忆的机制。本研究采用C.秀丽线虫分子 遗传学、成像、行为测定以及代谢物的生化测量。