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

睾酮与 2 型糖尿病在阿尔茨海默病中的相互作用

• 批准号: 8325047
• 负责人: CHRISTIAN J PIKE
• 金额: $ 33.21万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8325047
• 关键词: Acute; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Androgen Therapy; Androgens; Animal Model; Applications Grants; Behavioral; Brain; Development; Diabetes Mellitus; Diet; Effectiveness; Epidemiology; Fostering; Genetic; Health; Hippocampus (Brain); Individual; Inflammation; Knowledge; Lead; Link; Malignant neoplasm of prostate; Measures; Metabolic; Modeling; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pathology; Performance; Persons; Population; Preventive Intervention; Rattus; Rattus norvegicus; Regulation; Risk; Risk Factors; Rodent Model; Role; Signal Pathway; Signal Transduction; Testing; Testosterone; Therapeutic; Transgenic Organisms; abeta accumulation; age related; design; high risk; improved; indexing; male; men; mouse model; neuropathology; normal aging; prevent; reproductive; research study; selective androgen receptor modulator; tau Proteins; tau phosphorylation

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.

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）发展的危险因素。两个这样的危险因素是男性与年龄相关的睾丸激素减少和2型糖尿病（T2D）。目前尚不清楚这两种情况是如何增加患AD的风险的。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。在这个应用中，我们将评估正常的，与年龄相关的睾丸激素损失不仅通过对大脑的直接影响而且通过促进T2D增加AD发病机制的假设。同样，我们将研究补充假设，即T2D通过降低睾丸激素水平直接增加AD病理。因此，睾酮丢失和T2D被认为是相互关联的条件，它们共同增加AD的发展。从机制上讲，低睾酮和T2D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T2D通过调节阿尔茨海默病病理这三个方面的细胞信号通路的相互作用共同增加了阿尔茨海默病的发病机制。为了研究这些假设，我们提出了三个具体目标。在Aim 1中，我们将研究实验性诱导T2D对衰老和AD动物模型中睾酮和AD水平的影响。在Aim 2中，我们将研究实验诱导的低睾酮对T2D动物模型中T2D和AD测量的影响。在目标1和目标2中，我们还将研究年龄在低睾酮和T2D之间确定的相互作用关系中的作用。最后，在Aim 3中，我们将评估睾丸激素之间相互作用的候选机制，重点关注调节β -淀粉样蛋白积累、tau过度磷酸化和炎症的信号通路。我们的研究的完成将描述和机制定义睾酮和T2D之间的关系，以及它们如何协同作用促进AD的发展，这些知识将对理解和预防老年男性AD具有宝贵的价值。