IMPACT OF REDUCED NEUROSTEROIDS IN BRAIN AGING

项目摘要/摘要 很大比例的老龄化人口经历了认知能力下降，其中包括 学习、记忆、处理速度和执行功能。尽管已经有大量的研究表明 认知功能减退的病因随年龄增长，导致认知功能减退的具体机制仍然存在 难以捉摸。这种知识的缺乏严重限制了有效治疗干预措施的发展。 神经类固醇是通过与配体门控相互作用来改变神经元兴奋性的类固醇。 通道或其他细胞表面受体。它们还具有通过经典基因影响基因表达的能力 类固醇激素受体。许多神经类固醇是由孕酮(PRG)通过 已知的类固醇生成酶在神经元和神经胶质细胞中都有表达，包括但不限于， 糖皮质激素(CORT)、雌激素(E)、睾酮(T)和别孕酮。先前的研究表明， 在认知功能受损的几种神经退行性疾病模型中，别孕酮减少 都是显而易见的。应用别孕酮改善阿尔茨海默病模型小鼠的认知功能 阿尔茨海默病(AD)和尼曼-匹克C病(NPC)。然而，很少有研究评估大脑是否 别孕酮水平随着年龄的增长而下降，据我们所知，还没有研究评估其 对与年龄相关的认知能力下降的贡献。本申请中提供的LC/MS分析表明 雌雄小鼠脑组织中别孕酮的含量均显著下降。我们的初步数据显示 一次注射别孕酮显著增加神经发生和改善学习和 衰老小鼠的记忆。重要的是，炎性细胞因子已被证明可以调节PRG的代谢。 外周的酶，但它们在大脑中调节别孕酮的作用尚不清楚。这个 这一应用的假设是，与年龄相关的炎性细胞因子的增加改变了血管活性 PRG代谢酶导致别孕酮下降，神经再生减少， 老龄小鼠的认知功能障碍。提出了三个目标：1)确定特定的细胞内 控制与年龄相关的别孕酮下降的机制和替代的后果，2) 研究别孕酮是否促进神经干细胞(NSC)的增殖和/或NSC存活，以及 这种增加是通过旁分泌IGF-1水平的增加而调节的。

Project Summary/Abstract A large percentage of the aging population experiences cognitive decline, which includes impairments in learning, memory, processing speed, and executive function. Although there has been intensive research into the etiology of cognitive decline with age, the specific mechanisms responsible for cognitive impairment remain elusive. This lack of knowledge severely limits the development of effective therapeutic interventions. Neurosteroids are steroids that have the ability to alter neuronal excitability through interaction with ligand-gated channels or other cell surface receptors. They also have the ability to affect gene expression through classical steroid hormone receptors. Many neurosteroids are synthesized from progesterone (PRG) through a network of steroidogenic enzymes known to be expressed in both neurons and glial cells and include, but are not limited to, glucocorticoids (CORT), estrogens (E), testosterone (T) and allopregnanolone. Previous research indicates that allopregnanolone decreases in several models of neurodegenerative disease where deficits in cognitive function are evident. Administration of allopregnanolone improves cognitive function in mouse models of Alzheimer’s disease (AD) and Niemann-Pick C disease (NPC). Nevertheless, few studies have assessed whether brain levels of allopregnanolone levels decrease with age, and to our knowledge, no studies have assessed its contribution to age-related cognitive decline. LC/MS analysis presented in this application reveal that allopregnanolone declines significantly in brain tissue of male and female mice. Our preliminary data indicate that a single injection of allopregnanolone significantly increases neurogenesis and improves learning and memory in aged mice. Importantly, inflammatory cytokines have been shown to regulate PRG metabolizing enzymes in the periphery but their role in regulating allopregnanolone in the brain remain unknown. The hypothesis of this application is that the age-related increase in inflammatory cytokines alters activity of PRG metabolizing enzymes resulting in a decline in allopregnanolone, reduced neurogenesis and cognitive impairment in aged mice. Three aims are proposed: 1) Determine the specific intra-cellular mechanisms governing the age-related decline in allopregnanolone and consequences of replacement, 2) Investigate whether allopregnanolone increases neural stem cell (NSC) proliferation and/or NSC survival, and if this increase is mediated through increases in paracrine IGF-1 levels.