A healthy brain aging strategy to restore insulin signaling and Ca homeostasis

 描述（由申请人提供）： 外周代谢失调似乎增加了认知能力随年龄增长而下降的风险，并增加了对痴呆性神经退行性疾病如阿尔茨海默病的易感性。然而，代谢失调和年龄相关的认知功能障碍之间的关系的途径和机制尚未明确界定。在这里，我们提出，在大脑中的胰岛素抵抗可以不稳定的严格监管的过程，维持正常的钙稳态的神经元，导致神经元功能障碍和认知受损。脑相关神经元钙调节异常是一种公认的导致神经功能障碍和认知能力下降的机制，我们和其他人已经广泛表征了这种对学习和记忆重要的脑结构功能障碍。有趣的是，胰岛素抵抗的外周组织也显示钙调节异常，并为大脑中的类似关系提供支持证据。在上一个融资周期，我们 发现了海马神经元中代谢失调和钙信号改变之间先前未被认识的联系。总之，这些研究结果为以下观点提供了支持：通过提高胰岛素水平的策略克服海马体中的胰岛素抵抗将重建神经元钙稳态。几种创新的方法将被用来增加大脑胰岛素信号老化。具体而言，我们将1）利用鼻内胰岛素递送来增加体内脑胰岛素受体处的胰岛素可用性，2）通过组成型活性人胰岛素受体突变体（β亚基）的AAV介导的表达来增加脑中的胰岛素受体信号传导，以及3）通过使用新的药理学策略来增加内源性胰岛素受体运输。在F344大鼠衰老模型中使用这些方法，我们将使用不同的行为范式研究认知功能。在这些动物的海马组织中，我们将使用单细胞电生理学/成像直接测量钙状态（记录钙依赖性电位和钙成像），并使用分子/生化测定补充这些研究。为了确定增加大脑中的胰岛素是否会影响其他独立于Ca 2+的途径，我们还将定量p-Akt信号传导、酪氨酸磷酸化、葡萄糖稳态（葡萄糖成像）和脂联素水平。2型糖尿病在老年人中已达到流行病的比例，约占2600万人，对我们的卫生保健系统造成1750亿美元的损失（CDC统计数据）。我们的研究旨在确定增强大脑中的胰岛素作用是否可以减轻衰老中认知能力下降的负担，并有助于保持健康的认知功能。我们的研究结果将为相关的临床研究提供信息，并可能对老龄化人口产生重大影响，特别是对那些患神经退行性疾病（如阿尔茨海默病）风险增加的人。这项工作是面向临床的，并直接解决了NIA的使命之一，通过建立新的目标，治疗认知能力下降和/或痴呆症的大脑老化。

 DESCRIPTION (provided by applicant): Peripheral metabolic dysregulation appears to increase the risk for cognitive decline with aging and susceptibility to dementing neurodegenerative disorders such as Alzheimer's disease. However, the pathways and mechanisms underlying the relationship between metabolic dysregulation and age-related cognitive impairment are not clearly defined. Here we propose that insulin resistance in the brain can destabilize tightly regulated processes which maintain normal calcium homeostasis in neurons resulting in neuronal dysfunction and impaired cognition. Age-related neuronal calcium dysregulation is a well-recognized mechanism contributing to neurologic dysfunction and cognitive decline and we and others have extensively characterized this dysfunction in brain structures important for learning and memory. Interestingly, peripheral tissues that are insulin resistant also show calcium dysregulation and provide supporting evidence for a similar relationship in the brain. In the prior funding cycle, we identified a previously unrecognized link between metabolic dysregulation and altered calcium signaling in hippocampal neurons. Together, these findings provide support for the notion that overcoming insulin resistance in the hippocampus with insulin-raising strategies will reestablish neuronal calcium homeostasis. Several innovative approaches will be used to increase brain insulin signaling in aging. Specifically, we will 1) utilize intranasal insulin delivery to increas insulin availability at the brain insulin receptor in vivo, 2) increase insulin receptor signaling n the brain via AAV-mediated expression of a constitutively active human insulin receptor mutant (β subunit), and 3) increase endogenous insulin receptor trafficking through the use of a novel pharmacologic strategy. Using these approaches in the F344 rat model of aging, we will investigate cognitive functions using different behavioral paradigms. In hippocampal tissue from these animals, we will use single cell electrophysiology/imaging to directly measure calcium status (recordings of calcium-dependent potentials and calcium imaging), and complement these studies with molecular/biochemical assays. To determine whether increasing insulin in the brain affects other pathways independent of Ca2+, we will also quantify p-Akt signaling, tyrosine phosphorylation, glucose homeostasis (glucose imaging), and adiponectin levels. Type 2 diabetes has reached epidemic proportions among older adults accounting for approximately 26 million people and a $175 billion dollar toll to our health care system (CDC statistics). Our studies are designed to determine whether enhancing insulin action in the brain reduces the burden of cognitive decline in aging and helps to maintain healthy cognitive function. The outcomes from our studies will inform related clinical studies and may have significant impact for the aging population, especially for those at increased risk for neurodegenerative diseases such as Alzheimer's disease. This work is clinically-oriented and directly addresses one of the missions of the NIA by establishing novel targets for the treatment of cognitive decline and/or dementia in brain aging.