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

睾酮与 2 型糖尿病在阿尔茨海默氏病路径中的相互作用

基本信息

批准号：
8188180
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
项目类别：
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/8188180
关键词：
Acute Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease risk Androgen Therapy Androgens Animal Model Applications Grants Behavioral Brain Development Diabetes Mellitus 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

项目摘要

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，已经将几种疾病确定为发展阿尔茨海默氏病（AD）的风险因素。两个这样的危险因素是男性和2型糖尿病（T2D）的年龄相关睾丸激素丧失。目前尚不清楚这两个条件如何增加AD的风险。此外，尚不清楚这些条件是独立还是相关的风险因素。在此应用中，我们将评估以下假设：正常的，与年龄相关的睾丸激素损失不仅通过直接对大脑的影响，而且通过促进T2D来增加AD发病机理。同样，我们将研究以下互补假设：T2D直接增加AD病理以及降低睾丸激素水平。因此，假定睾丸激素丢失和T2D是相互关联的条件，结合起来会增加AD的发展。从机械上讲，低睾丸激素和T2D都独立影响AD神经病理学的关键特征，包括β-淀粉样蛋白的积累，TAU高磷酸化和炎症。我们假设睾丸激素和T2D通过调节AD病理的这三个方面的细胞信号通路中的相互作用，从而增加了AD发病机理。为了研究这些假设，我们提出了三个具体目标。在AIM 1中，我们将研究实验诱导的T2D对睾丸激素水平和AD水平的影响。在AIM 2中，我们将研究实验诱导的低睾丸激素对T2D动物模型中T2D和AD度量的影响。在两个目标1和2中，我们还将研究衰老对低睾丸激素和T2D之间的关系相互作用的作用。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，重点是调节β-淀粉样蛋白积累，TAU高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丸激素与T2D之间的关系，以及它们如何合作地促进AD的发展，这对于理解和预防衰老男人的AD将是无价的。