Investigating the relationship between age-related skeletal muscle insulin resistance and cognitive impairment

摘要 在本ADRD附录中，我们建议扩大NIH/NIA 1R15AG073922目标1的工作范围 (2024年到期)。受资助的R15的工作范围集中在理解 造成与年龄相关的胰岛素抵抗的骨骼肌。具体地说，父母奖助金的目标1审查 在AS160磷酸化水平上促进年龄相关性骨骼肌胰岛素抵抗的机制 胰岛素信号级联中最远端的蛋白质。阿尔茨海默病和2型糖尿病 目前排在65岁以上个人死亡原因的前7位(CDC)。胰岛素 耐药性已被公认为2型糖尿病的主要致病因素。同样， 轻度认知障碍往往是阿尔茨海默病发展的前兆。虽然每个条件 传统上被认为是他们各自疾病的早期发病机制，越来越多的证据表明 提示胰岛素抵抗在认知障碍的发展中起关键作用，导致 阿尔茨海默氏症。据报道，患有轻度认知障碍的老年人存在胰岛素抵抗， 阿尔茨海默氏症。此外，胰岛素抵抗与受影响区域的脑萎缩有关。 由早期阿尔茨海默氏症引起。骨骼肌是胰岛素介导的葡萄糖摄取的主要靶点；因此， 它是研究年龄相关性骨骼肌胰岛素抵抗与年龄相关性的理想组织。 认知障碍。不幸的是，目前还没有已知的研究调查骨骼与 与年龄相关的胰岛素抵抗(父母补助)和认知障碍的肌肉机制； 因此，我们提出了两个主要证明的具体目标，以批判性地检查两者之间的联系。 对老化过程产生负面影响的重要条件。目标1将确定骨骼肌受损 胰岛素刺激的AS160磷酸化与学习/记忆认知域的减少有关， 老年人的精神运动处理速度和执行功能，以及患有MCI的老年人是否会 与认知正常的老年人相比，AS160的磷酸化水平较低。目标2将决定是否 骨骼肌胰岛素刺激AS160磷酸化受损与认知生物标志物相关 损伤(p-181 tau、神经丝轻链、β-淀粉样蛋白-42、酰肉碱和apoE4等位基因)。至 为了实现这些目标，我们将在拟议的工作范围内增加一批患有MCI(n=12)的老年人 父母批准并增加认知功能测试和遗传apoE4等位基因测试 1年补助金(12名老年MCI和12名认知健康的老年人从父母津贴)。此外，所有存储的 血液(12名老年人补充MCI，12名老年人和12名青少年认知健康)将由父母资助 接受认知障碍的生物标志物测试。在完成本补充文件后，我们预计将拥有 提供了证明骨骼肌葡萄糖代谢受损之间存在联系的主要证据， 具体损害胰岛素刺激的AS160磷酸化和认知障碍。此外，这一点 补充课程将为学生提供一个接触翻译和多学科研究的机会， 同时了解与年龄相关的健康问题。

Abstract In this ADRD supplement, we propose to expand the scope of work in Aim 1 of our NIH/NIA 1R15AG073922 (expires 2024). The scope of work in the funded R15 centers on understanding the cellular mechanisms in skeletal muscle that contribute to age-related insulin resistance. Specifically, Aim 1 of the parent grant examines mechanisms contributing to age-related skeletal muscle insulin resistance at the level of AS160 phosphorylation, the most distally located protein in the insulin signaling cascade. Alzheimer’s disease and Type 2 diabetes are currently ranked amongst the top 7 causes of death for individuals over the age of 65 years (CDC). Insulin resistance has been well-recognized as the primary contributor for the development of type 2 diabetes. Similarly, mild cognitive impairment is often a precursor for the development of Alzheimer’s disease. While each condition has been traditionally thought of as the early pathogenesis for their respective disease, growing evidence suggests that insulin resistance plays a critical role in the development of cognitive impairments leading to Alzheimer’s disease. Insulin resistance has been reported in older adults with mild cognitive impairment and Alzheimer’s disease. Additionally, insulin resistance has been associated with brain atrophy in regions affected by early Alzheimer’s disease. Skeletal muscle is the main target of insulin-mediated glucose uptake; therefore, it is the ideal tissue to investigate the relationships between age-related skeletal muscle insulin resistance and cognitive impairment. Unfortunately, no known research has investigated the relationship between the skeletal muscle mechanisms contributing to age-related insulin resistance (parent grant) and cognitive impairment; therefore, we propose two proof-of principal specific aims to examine the nexus between these critically important conditions negatively impacting the aging process. Aim 1 will determine if impaired skeletal muscle insulin-stimulated AS160 phosphorylation is related to reduced cognitive domains of learning/memory, psychomotor processing speed, and executive functioning in older adults, and whether older adults with MCI will have lower AS160 phosphorylation compared to older adults that are cognitively normal. Aim 2 will determine if impaired skeletal muscle insulin-stimulation of AS160 phosphorylation is associated with biomarkers of cognitive impairment (p-181 tau, neurofilament light chain, beta-amyloid-42, acylcarnitines, and the apoE4 allele). To accomplish these aims we will add a cohort of older adults with MCI (n=12) to the proposed scope of work in the parent grant and add cognitive function testing and genetic apoE4 allele testing to all aged adults enrolled during the 1-year supplement (n=12 aged MCI and n=12 aged cognitively healthy from parent grant). Further, all stored blood (n=12 aged MCI from supplement, n=12 aged and n=12 young cognitively healthy from parent grant) will be tested for biomarkers of cognitive impairment. At the completion of this supplement, we expect to have provided proof-of principal demonstrating a link between impaired skeletal muscle glucose metabolism, specifically impaired insulin-stimulated AS160 phosphorylation and cognitive impairments. Additionally, this supplement will provide an opportunity for students to be exposed to translational and multidisciplinary research, while learning about the age-related health concerns.