Androgens and Alzheimer's Disease

雄激素和阿尔茨海默病

• 批准号: 6868647
• 负责人: CHRISTIAN J PIKE
• 金额: $ 26.65万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6868647
• 关键词: Alzheimer' s disease; aging; androgen receptor; androgens; biological signal transduction; clinical research; disease /disorder model; disease /disorder proneness /risk; genetically modified animals; hormone metabolism; hormone regulation /control mechanism; human subject; immunocytochemistry; laboratory mouse; laboratory rat; male; neuroendocrine system; neuroprotectants; polymerase chain reaction; protein structure function; tissue /cell culture

Abundant evidence suggests that the depletion of estrogen in postmenopausal women is a significant risk factor for the development of Alzheimer's disease (AD). As a normal consequence of aging, men also exhibit depletion of their primary sex steroid hormone, testosterone. The reduction in men's androgen levels is manifested clinically as impaired function in numerous androgen-sensitive tissues throughout the body, including the brain. Based on recent evidence from our laboratory, we propose that two neural functions of androgens are promotion of neuron viability and regulation of beta-amyloid protein (A-beta). We predict that impairment of these androgen functions occurring as a result of normal, age-related androgen depletion will place the brain at increased risk for the development of Alzheimer's disease. To investigate this hypothesis, we propose three Specific Aims that utilize complementary cell culture, animal model, and human subjects paradigms. In the Aim 1, we will investigate our hypothesis that androgens are endogenous regulators of neuron viability. Proposed studies will assess the role of androgen receptor in neuroprotection as well as elucidate the responsible downstream signaling cascades. Further, we will examine how age-related androgen depletion affects neuronal vulnerability to injury. In Aim 2, we investigate the hypothesized role of androgens as endogenous modulators of AE, levels. By experimental manipulation of androgen status in animal models, we will evaluate our hypothesis that androgen depletion will result in increased levels of A-beta. Mechanistic studies will evaluate the contributions of androgen receptor activation and androgen regulation of A- beta-catabolizing enzymes. Together, we anticipate that Aims 1 and 2 will establish that androgens have beneficial, protective actions in brain and that androgen depletion places the brain at risk for degeneration and disease. In Aim 3, we will further evaluate this hypothesis by both investigating how manipulation of androgen status affects progression of AD-like neuropathology in a transgenic mouse model of Alzheimer's disease. and examining the relationships between human aging, brain levels of A-beta and androgens, and AD status. Together, we believe these novel and timely studies will begin an important evaluation of interactions between normal male aging events, neuroprotection, A-beta regulation, and the risk of developing Alzheimer's disease.

大量证据表明，绝经后妇女雌激素的消耗是阿尔茨海默病（AD）发展的一个重要危险因素。作为衰老的正常结果，男性也表现出他们的主要性类固醇激素睾酮的消耗。男性雄激素水平的降低在临床上表现为全身许多雄激素敏感组织（包括大脑）的功能受损。基于我们实验室最近的证据，我们提出雄激素的两个神经功能是促进神经元活力和调节β-淀粉样蛋白（A-β）。我们预测，由于正常的、与年龄相关的雄激素耗竭而发生的这些雄激素功能的损害将使大脑患阿尔茨海默病的风险增加。为了研究这一假设，我们提出了三个具体的目标，利用互补的细胞培养，动物模型和人类受试者的范例。在目标1中，我们将研究我们的假设，即雄激素是神经元活力的内源性调节因子。 拟开展的研究将评估雄激素受体在神经保护中的作用，并阐明负责的下游信号级联。此外，我们将研究年龄相关的雄激素耗竭如何影响神经元损伤的脆弱性。在目的2中，我们研究雄激素作为AE水平的内源性调节剂的假设作用。通过动物模型中雄激素状态的实验操作，我们将评估我们的假设，即雄激素耗竭将导致A-β水平升高。 机制研究将评估雄激素受体激活和A-β-分解代谢酶的雄激素调节的作用。总之，我们预期目标1和2将确定雄激素在大脑中具有有益的保护作用，雄激素耗竭将使大脑处于变性和疾病的风险中。在目标3中，我们将通过研究雄激素状态的操纵如何影响阿尔茨海默病转基因小鼠模型中AD样神经病理学的进展来进一步评估这一假设。以及研究人类衰老、大脑A-β和雄激素水平与AD状态之间的关系。总之，我们相信这些新颖而及时的研究将开始对正常男性衰老事件、神经保护、A-β调节和阿尔茨海默病风险之间的相互作用进行重要评估。