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 目前缺乏理论方法来改善特征的认知下降 神经退行性疾病，例如阿尔茨海默氏病（AD）和AD相关痴呆症（ADRDS）。缺陷 学习和记忆也有助于。我们一直在研究kynurenic酸，kyna，一种色氨酸 衍生的代谢产物，作为秀丽隐杆线虫中代谢，衰老和学习和记忆的联系。有 来自包括秀丽隐杆线虫和小鼠在内的多种物种的令人信服的证据，这些证据降低了Kyna的改善 在这种神经调节代谢产物中增加的学习和记忆力有害。在两个C中 秀丽隐杆线虫和小鼠随着年龄的增长而积聚。 Kyna积累还涉及人类衰老和 神经退行性疾病，包括AD和ADRD。我们以前证明了使用遗传操作 降低Kyna水平可大大改善老年秀丽隐杆线虫以及C中的学习记忆。 秀丽隐杆线虫模型。这些改进是由于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 跨系统发育的记忆。这些发现促使我们寻求分子机制和药物 减少Kyna的试剂。我们已经确定了Androst-5-Ene-3β，17β-二醇（ADIOL），A C19立体骑马，为 秀丽隐杆线虫中Kyna的潜在减少和学习能力的增强子。我们已经证明了 Adiol的效果取决于NHR-91，NHR-91是序列和功能性的转录因子 与哺乳动物雌激素受体β，ERβ的同源性。这些发现引人入胜，有两个关键原因：（i） 长期以来在哺乳动物中识别出Adiol的存在，但是该类固醇的生理功能 骑马的理解很少，（ii）有令人信服的证据表明ERβ在 哺乳动物具有许多有益的效果，包括改善学习和记忆，但基础 机制是未知的。我们假设Adiol用作内源配体以激活ERβ样 核马酮受体反过来导致Kyna减少以促进学习和记忆。我们的 具体的目的是严格确定Adiol在衰老和C中的学习和记忆中的作用。 神经退行性的秀丽隐杆线模型，设计了从 秀丽隐杆线虫，研究NHR-91作为Adiol和Kyna之间的机械联系的作用，并探索三个 假设与Adiol的物理作用有关，包括其在衰老中的作用，作为一种联系的机制 营养的感觉途径通过Kyna进行学习和记忆，作为一种联系的机制 学习和记忆机制的生殖能力。该投资员工C.秀丽隐杆线分子 遗传学，成像，行为测定以及代谢物的生化测量。