Interactions between Testosterone and Type 2 Diabetes in Alzheimer's Disease

描述（由申请人提供）：近年来，几种情况已被确定为阿尔茨海默病（AD）发展的风险因素。两个这样的风险因素是年龄相关的男性睾酮损失和2型糖尿病（T2 D）。目前尚不清楚这两种情况如何增加AD的风险。此外，尚不清楚这些情况是否作为独立或相关的风险因素发挥作用。在本申请中，我们将评估以下假设：正常的、与年龄相关的睾酮损失不仅通过对大脑的直接影响而且通过促进T2 D来增加AD发病机制。同样，我们将研究T2 D直接增加AD病理学以及通过降低睾酮水平的补充假设。因此，假设睾酮损失和T2 D是相互关联的条件，其组合协同增加AD的发展。从机制上讲，低睾酮和T2 D都独立影响AD神经病理学的关键特征，包括β-淀粉样蛋白积累、tau蛋白过度磷酸化和炎症。我们假设睾酮和T2 D通过调节AD病理这三个方面的细胞信号通路的相互作用协同增加AD发病机制。为了研究这些假设，我们提出了三个具体目标。在目的1中，我们将研究实验诱导的T2 D对衰老和AD动物模型中睾酮和AD水平的影响。在目的2中，我们将研究实验诱导的低睾酮对T2 D动物模型中T2 D和AD测量的影响。在目标1和2中，我们还将研究衰老对低睾酮和T2 D之间已确定的关系相互作用的作用。最后，在目标3中，我们将评估睾酮之间相互作用的潜在机制，重点是调节β-淀粉样蛋白积累，tau蛋白过度磷酸化和炎症的信号通路。我们的研究的完成将表征和机械定义睾酮和T2 D之间的关系，以及它们如何协同作用，以促进AD的发展，知识，这将是非常宝贵的理解和预防老年男性AD。

DESCRIPTION (provided by applicant): In recent years, several conditions have been identified as risk factors for the development of Alzheimer's disease (AD). Two such risk factors are age-related testosterone loss in men and type 2 diabetes (T2D). It is unclear how these two conditions increase the risk for AD. Further, it is not known whether these conditions function as independent or related risk factors. In this application, we will evaluate the hypothesis that normal, age-related testosterone loss increases AD pathogenesis not only by direct effects on brain but also by promoting T2D. Similarly, we will investigate the complementary hypothesis that T2D increases AD pathology directly as well as by reducing testosterone levels. Thus, testosterone loss and T2D are postulated to be interrelated conditions that, in combination, cooperatively increase development of AD. Mechanistically, both low testosterone and T2D independently affect key features of AD neuropathology, including beta-amyloid accumulation, tau hyperphosphorylation, and inflammation. We hypothesize that testosterone and T2D cooperatively increase AD pathogenesis by interactions in the cell signaling pathways that regulate these three aspects of AD pathology. To investigate these hypotheses, we propose three specific aims. In Aim 1, we will investigate the effects of experimentally induced T2D on levels of testosterone and AD in animal models of aging and AD. In Aim 2, we will investigate the effects of experimentally-induced low testosterone on measures of T2D and AD in animal models of T2D. In both Aims 1 and 2, we will also examine the role of aging on identified relationships interactions between low testosterone and T2D. Finally, in Aim 3 we will evaluate candidate mechanisms underlying interactions between testosterone, focusing on signaling pathways that regulate beta-amyloid accumulation, tau hyperphosphorylation, and inflammation. Completion of our studies will characterize and mechanistically define relationships between testosterone and T2D and how they cooperatively act to promote development of AD, knowledge that will be invaluable in understanding and preventing AD in aging men.