IMPACT OF REDUCED NEUROSTEROIDS IN BRAIN AGING

项目总结/摘要 很大比例的老龄化人口经历认知能力下降，其中包括 学习记忆处理速度和执行功能虽然有深入的研究， 随着年龄的增长，认知能力下降的病因，负责认知障碍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。 神经甾体是具有通过与配体门控的神经元相互作用来改变神经元兴奋性的能力的甾体。 通道或其他细胞表面受体。它们也有能力通过经典的免疫调节作用影响基因表达。 类固醇激素受体许多神经类固醇是由孕酮（PRG）通过一个网络合成的。 已知在神经元和神经胶质细胞中表达的类固醇生成酶包括，但不限于， 糖皮质激素（CORT）、雌激素（E）、睾酮（T）和别孕烯醇酮。先前的研究表明， 别孕烯醇酮在几种神经退行性疾病模型中减少， 明显的情况给予别孕烯醇酮改善阿尔茨海默病小鼠模型的认知功能 疾病（AD）和尼曼-匹克C病（NPC）。然而，很少有研究评估大脑是否 别孕烯醇酮水平随年龄增长而下降，据我们所知，没有研究评估其 与年龄相关的认知能力下降。本申请中提出的LC/MS分析显示， 雄性和雌性小鼠的脑组织中别孕烯醇酮显著下降。我们的初步数据显示 单次注射别孕烯醇酮显著增加神经发生并改善学习， 老年老鼠的记忆力重要的是，已经显示炎性细胞因子调节PRG代谢， 在外周中的酶，但它们在调节大脑中的别孕烯醇酮的作用仍然未知。的 本申请的假设是炎性细胞因子的年龄相关性增加改变了 PRG代谢酶导致别孕烯醇酮下降，神经发生减少， 老年小鼠的认知障碍。提出了三个目标：1）确定细胞内的特异性 控制年龄相关的别孕烯醇酮下降的机制和替代的后果，2） 研究别孕烯醇酮是否增加神经干细胞（NSC）增殖和/或NSC存活，以及 这种增加是通过旁分泌IGF-1水平的增加介导的。

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.