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

老龄化人口的规模在世界范围内达到创纪录的水平，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））的个体的数量平行增加。多种因素使个体易患认知障碍和痴呆，包括肥胖、代谢综合征、前驱糖尿病和糖尿病，其发病率在世界范围内也在增长。由于几乎没有可用的治疗方法，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，特别是在代谢失衡的早期阶段，例如中年肥胖和进展为坦率糖尿病之前的前驱糖尿病。炎症是衰老、肥胖、前驱糖尿病、糖尿病和认知障碍（包括AD/ADRD）的共同特征。炎症机制可能通过促进早期或增加炎症（慢性低度炎症）而发挥特别重要的作用。可能导致炎症的一种特定的先天性炎症机制是双链DNA（dsDNA）传感cGAS/STING途径。cGAS/STING在肥胖、代谢综合征、前驱糖尿病和糖尿病的外周组织中失调。该途径响应于来自细菌或病毒的胞质dsDNA或由于核或线粒体应激而释放的胞质dsDNA，并上调促炎细胞因子。我们假设肥胖和前驱糖尿病进展期间的血脂异常和胰岛素抵抗触发炎症通路，包括cGAS/STING，其在中枢神经系统（CNS）内加剧和传递炎症信号。我们还预计，作为CNS的主要免疫细胞，小胶质细胞介导这种炎症传递，部分通过细胞外囊泡炎症串扰，进一步恶化神经和认知结果。我们将通过以下方式检验我们的假设：1）确定cGAS/STING和炎症环境在中年至晚年肥胖和前驱糖尿病诱导的认知障碍的进展期间的作用，和3）研究衰老期间肥胖和前驱糖尿病诱导的认知障碍中CNS中细胞外囊泡介导的cGAS/STING炎性串扰机制。这项研究将确定炎症和cGAS/STING通路在肥胖和前驱糖尿病进展过程中如何波动，以及它们如何导致认知障碍，从而导致AD/ADRD。此外，该研究将确定疾病修饰靶点，也许更重要的是，这些潜在疗法的理想治疗窗口，用于早期干预和预防AD/ADRD。

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.