Midlife obesity and prediabetes trigger later life cognitive decline through central nervous system inflammaging and innate immune dysregulation of cGAS/STING

中年肥胖和糖尿病前期通过中枢神经系统炎症和 cGAS/STING 的先天免疫失调引发晚年认知能力下降

• 批准号: 10370457
• 负责人: Sarah Elzinga
• 金额: $ 11.06万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370457
• 关键词: Acute; Affect; Age; Age-associated memory impairment; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease related dementia; Anti-Inflammatory Agents; Bacteria; Brain; Cell Aging; Cells; Child; Chronic; Clinical; Cognition; Cognitive; Communication; Complement; Complication; Cytokine Gene; Data; Dementia; Diabetes Mellitus; Diet; Disease; Dyslipidemias; Early Intervention; Early treatment; Elderly; Etiology; Event; Foundations; Future; Gene Expression; Goals; High Fat Diet; Hippocampus (Brain); Immune; Immune system; Impaired cognition; In Vitro; Individual; Inflammaging; Inflammation; Inflammatory; Insulin; Insulin Resistance; Knockout Mice; Knowledge; Link; Measures; Mediating; Mentors; Metabolic; Metabolic dysfunction; Metabolic syndrome; Microglia; Mitochondria; Modeling; Molecular; Mus; Nervous System Trauma; Neuraxis; Neurologic; Neurons; Nuclear; Obesity; Outcome; Pathogenesis; Pathologic; Pathway interactions; Peripheral; Phase; Play; Population; Positron-Emission Tomography; Prediabetes syndrome; Predisposing Factor; Proteins; Research; Research Personnel; Role; Saturated Fatty Acids; Signal Transduction; Stimulator of Interferon Genes; Stress; Techniques; Testing; Therapeutic; Time; TimeLine; Tissues; Training; United States; Virus; aging population; career; cognitive change; cognitive development; cytokine; druggable target; ds-DNA; effective therapy; extracellular vesicles; in vivo; inflammatory milieu; interest; knockout animal; loss of function; middle age; mouse model; novel; obese patients; single-cell RNA sequencing; stem; targeted treatment; transcriptomics; translatable strategy; transmission process

The size of the aging population is reaching record levels worldwide, causing a parallel increase in the number of individuals with cognitive impairment and dementia, including Alzheimer’s Disease and Alzheimer’s Disease- Related Dementias (AD/ADRD). Multiple factors predispose individuals to the development of cognitive impairment and dementia, including obesity, the metabolic syndrome, prediabetes, and diabetes, whose rates are also growing worldwide. With few to no available treatments, research is critical to understand the mechanisms by which these metabolic dysfunctions promote cognitive impairment and AD/ADRD with aging, especially during early phases of metabolic imbalance, such as in midlife obesity and in prediabetes before progression to frank diabetes. Inflammation is a common denominator across aging, obesity, prediabetes, diabetes, and cognitive impairment, including in AD/ADRD. Inflammatory mechanisms may play a particularly important role by promoting early or increased inflammaging, a chronic low-grade inflammation. One particular innate inflammatory mechanism that may be contributing to inflammaging is the double-stranded DNA (dsDNA) sensing cGAS/STING pathway. cGAS/STING is dysregulated in peripheral tissues in obesity, the metabolic syndrome, prediabetes, and diabetes. This pathway responds to cytosolic dsDNA from bacteria or viruses or released as a result of nuclear or mitochondrial stress and upregulates pro-inflammatory cytokines. We hypothesize that dyslipidemia and insulin resistance during the progression of obesity and prediabetes trigger inflammatory pathways, including cGAS/STING, that exacerbate and transmit inflammatory signals within the central nervous system (CNS). We also anticipate that as the primary immune cells of the CNS, microglia mediate this inflammatory transmission, in part via extracellular vesicle inflammatory crosstalk, further worsening neurologic and cognitive outcomes. We will test our hypothesis by: 1) establish the role of cGAS/STING and the inflammatory milieu during the progression of midlife to later life obesity- and prediabetes-induced cognitive impairment, 2) determine the role of microglial cGAS/STING in HFD-induced cognitive impairment in mid and later life, and 3) investigate extracellular vesicle mediated cGAS/STING inflammatory crosstalk mechanisms in the CNS in obesity- and prediabetes-induced cognitive impairment during aging. This study will establish how inflammation and the cGAS/STING pathway fluctuate during aging as obesity and prediabetes progress, and how they contribute to cognitive impairment that overtime leads to AD/ADRD. Additionally, the study will identify disease-modifying targets and, perhaps more importantly, ideal therapeutic windows for these potential therapies for early intervention and the prevention of AD/ADRD.

全球人口老龄化规模达到创纪录水平，导致患有认知障碍和痴呆症（包括阿尔茨海默病和阿尔茨海默病相关痴呆症（AD/ADRD））的人数同步增加。多种因素使个体容易患上痴呆症。认知障碍和痴呆，包括肥胖、代谢综合征、糖尿病前期和糖尿病，其发病率在世界范围内也在不断增长，但由于可用的治疗方法很少甚至没有，因此研究对于了解这些代谢功能障碍促进认知障碍和 AD/ADRD 的机制至关重要。和衰老，特别是在代谢失衡的早期阶段，例如中年肥胖和进展为糖尿病之前的糖尿病前期，炎症是衰老、肥胖、糖尿病前期、糖尿病和认知障碍（包括 AD/ADRD）的共同点。双链 DNA (dsDNA) 可能通过促进早期或增加炎症（一种慢性低度炎症）发挥特别重要的作用，可能导致炎症。感测 cGAS/STING 通路在肥胖、代谢综合征、糖尿病前期和糖尿病中的外周组织中失调。我们率先发现肥胖和糖尿病前期进展过程中的血脂异常和胰岛素抵抗会触发炎症途径，包括 cGAS/STING，从而加剧和传递中枢神经系统内的炎症信号。我们还预计，作为中枢神经系统的主要免疫细胞，小胶质细胞部分通过细胞外囊泡炎症串扰介导这种炎症传播，从而进一步恶化神经系统和认知结果：1）建立cGAS/STING 和炎症环境在中年到晚年肥胖和糖尿病前期诱发的认知障碍过程中的作用，2) 确定小胶质细胞 cGAS/STING 在HFD 诱发的中年和晚年认知障碍，以及 3) 研究细胞外囊泡介导的中枢神经系统中的 cGAS/STING 炎症串扰机制，以解决肥胖和糖尿病前期诱发的衰老过程中的认知障碍。随着肥胖和糖尿病前期的进展，通路在衰老过程中发生波动，以及它们如何导致认知障碍，进而导致AD/ADRD。此外，该研究还将确定疾病缓解目标，或许还有更多。重要的是，这些潜在疗法的理想治疗窗口可用于早期干预和预防 AD/ADRD。