Androgens and Alzheimer's Disease

雄激素和阿尔茨海默病

基本信息

批准号：
7379995
负责人：
CHRISTIAN J PIKE
金额：
$ 24.84万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
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/7379995
关键词：
Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid Proteins Amyloid beta-Protein Androgen Receptor Androgens Animal Model Animals Brain Clinical Cultured Cells Data Development Disease Enzymes Estrogens Evaluation Event Exhibits Female Functional disorder Gonadal Steroid Hormones Hormones Human Impairment Injury Laboratories Mediating Menopause Molecular Neprilysin Neuroendocrinology Neurons Neurophysiology - biologic function Neuroprotective Agents Pathogenesis Pathology Pathway interactions Postmenopause Receptor Activation Regulation Risk Risk Factors Rodent Role Signal Transduction Stanolone Syndrome Testing Testosterone Tissues Transgenic Organisms Woman age related aging brain base brain tissue human subject human tissue indexing male men mouse model neuropathology neuroprotection normal aging novel

项目摘要

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氏病（AD）发展的重要危险因素。由于衰老的正常结果，男性还表现出其原发性类固醇激素睾丸激素的耗竭。在包括大脑在内的许多雄激素敏感的组织中，男性雄激素水平的降低在临床上表现为临床上的功能受损。根据我们实验室的最新证据，我们建议雄激素的两个神经功能是促进神经元生存力和β-淀粉样蛋白（A-BETA）的调节。我们预测，由于正常的，与年龄有关的雄激素耗尽而导致的这些雄激素功能的损害会使大脑患阿尔茨海默氏病的发展风险增加。为了研究这一假设，我们提出了三个利用互补细胞培养，动物模型和人类受试者范式的特定目标。在目标1中，我们将研究雄激素是神经元生存力的内源性调节剂的假设。拟议的研究将评估雄激素受体在神经保护中的作用，并阐明负责任的下游信号级联反应。此外，我们将研究与年龄相关的雄激素耗竭如何影响神经元脆弱性损伤。在AIM 2中，我们研究了雄激素作为AE水平的内源调节剂的假设作用。通过对动物模型中雄激素状态的实验操纵，我们将评估我们的假设，即雄激素耗竭将导致A-beta水平升高。机械研究将评估A-β-代谢酶的雄激素受体激活和雄激素调节的贡献。我们预计目标1和2将确定雄激素在大脑中具有有益的保护作用，并且雄激素的耗竭使大脑处于退化和疾病的风险。在AIM 3中，我们将通过研究对雄激素状态的操纵如何影响Ad-like神经病理学的进展，进一步评估这一假设。并检查人类衰老，A-Beta和雄激素的大脑水平以及AD状态之间的关系。我们认为，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-beta调控以及患阿尔茨海默氏病的风险之间的相互作用进行重要评估。