Androgens and Alzheimer's Disease

大量证据表明，绝经后女性体内雌激素的缺乏是阿尔茨海默病(AD)发生的重要危险因素。作为衰老的正常后果，男性也会表现出他们主要的性类固醇荷尔蒙--睾酮的枯竭。男性雄激素水平的降低在临床上表现为全身许多对雄激素敏感的组织功能受损，包括大脑。根据我们实验室最近的证据，我们认为雄激素的两个神经功能是促进神经元活性和调节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枯竭而导致的这些雄激素功能的损害将使大脑处于阿尔茨海默病发展的更高风险中。为了研究这一假设，我们提出了利用互补细胞培养、动物模型和人类受试者范式的三个具体目标。在目标1中，我们将调查我们的假设，即雄激素是神经元活性的内源性调节因子。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枯竭如何影响神经元对损伤的易感性。在目标2中，我们研究了雄激素作为内源性调节因子对AE水平的假设作用。通过对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水平增加。机制研究将评估雄激素受体激活和雄激素调节A-β分解代谢酶的作用。总而言之，我们预计目标1和目标2将确定雄激素在大脑中具有有益的保护作用，雄激素枯竭使大脑处于退化和疾病的风险中。在目标3中，我们将通过在阿尔茨海默病转基因小鼠模型中研究雄激素状态的操纵如何影响AD样神经病理的进展来进一步评估这一假说。以及研究人类衰老、大脑A-β和雄激素水平以及AD状态之间的关系。总之，我们相信这些新颖和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发病风险之间的相互作用进行重要评估。

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.