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.

老龄化人口的规模正在全球达到创纪录的水平，导致认知障碍和痴呆症患者的数量平行增加，包括阿尔茨海默氏病和阿尔茨海默氏病与痴呆症相关的痴呆症（AD/ADRD）。多种因素使个体易受认知障碍和痴呆症的发展，包括肥胖症，代谢综合征，糖尿病前和糖尿病，其发生率在全球范围内也在增长。对于了解这些代谢功能障碍会促进认知障碍和衰老的AD/ADRD的机制，研究至关重要，尤其是在代谢失衡的早期阶段，例如中年肥胖症中的早期阶段，例如在中期肥胖症中，在糖尿病前期的前糖尿病前促进了认知障碍和AD/ADRD的机制至关重要。炎症机制可能通过促进早期或增加炎症（一种慢性低度炎症）来发挥特别重要的作用。可能导致炎症的一种特殊的先天炎症机制是双链DNA（DSDNA）感应CGA/STING途径。 CGA/STING在肥胖，代谢综合征，糖尿病前和糖尿病的外周组织中失调。该途径对细菌或病毒的胞质dsDNA反应或由于核或线粒体应激而释放，并上调促炎性细胞因子。我们假设在肥胖症和糖尿病前期进展过程中血脂异常和胰岛素抵抗会触发炎症途径，包括CGA/STING，这些途径加剧了中枢神经系统（CNS）内的炎症和传播炎症信号。我们还预计，作为中枢神经系统的主要免疫细胞，小胶质细胞介导这种炎症传播，部分通过细胞外囊泡炎症串扰，进一步令人担忧的神经系统和认知结果。我们将通过以下方式测试我们的假设：1）确定中期中期对以后的肥胖症和糖尿病前期认知障碍的进展过程中CGA/STING和炎症环境的作用，2）确定小胶质细胞CGA/ST在HFD诱发的中期和以后的生活中，以及CGAS的中等疾病/3）的作用。肥胖症和糖尿病前诱导的认知障碍的CNS中的串扰机制在衰老过程中。这项研究将确定随着肥胖和糖尿病前期的发展，感染和CGA/CGA/STING途径如何波动，以及它们如何促进加时性导致AD/ADRD的认知障碍。此外，该研究将确定改良疾病的靶标，也许更重要的是，这些潜在疗法的早期干预和预防AD/ADRD的理想治疗窗口。