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

全球老龄化人口的规模正在达到创纪录的水平，导致患有认知障碍和痴呆症的个人数量平行增加，包括阿尔茨海默病和阿尔茨海默病相关痴呆(AD/ADRD)。多种因素使个人易患认知障碍和痴呆，包括肥胖、代谢综合征、糖尿病前期和糖尿病，这些疾病的发病率在全球范围内也在不断上升。在几乎没有可用的治疗方法的情况下，研究对于了解这些代谢障碍促进认知障碍和AD/ADRD随年龄增长的机制至关重要，特别是在代谢失衡的早期阶段，如中年肥胖症和发展为直接糖尿病之前的糖尿病前期。炎症是衰老、肥胖、糖尿病前期、糖尿病和认知障碍的共同因素，包括AD/ADRD。炎症机制可能通过促进炎症的早期或加重而发挥特别重要的作用，炎症是一种慢性低度炎症。一种可能导致炎症的特殊先天炎症机制是双链DNA(DsDNA)感知cGAS/STIN途径。在肥胖、代谢综合征、糖尿病前期和糖尿病的外周组织中，cGAS/STIN表达异常。这一途径对细菌或病毒的胞浆dsDNA作出反应，或因核或线粒体应激而释放，并上调促炎细胞因子。我们假设，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/STIN，从而加剧并在中枢神经系统(CNS)内传递炎症信号。我们还预计，作为中枢神经系统的主要免疫细胞，小胶质细胞介导了这种炎症传递，部分是通过细胞外小泡炎症串扰，进一步恶化了神经和认知结果。我们将通过以下几个方面验证我们的假设：1)确定cGAS/STIN和炎症环境在中年肥胖和糖尿病前期认知损害中的作用，2)确定小胶质细胞cGAS/STIN在中老年HFD诱导的认知损害中的作用，以及3)研究细胞外小泡介导的cGAS/STIN炎症串扰机制在肥胖和糖尿病前期诱导的认知损害中的中枢神经系统在衰老过程中的作用。这项研究将建立炎症和cGAS/STING通路如何在衰老过程中随着肥胖和糖尿病前期的进展而波动，以及它们如何导致认知障碍，从而导致AD/ADRD。此外，这项研究将确定疾病修改目标，也许更重要的是，为这些潜在的治疗方法确定理想的治疗窗口，以便进行早期干预和预防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.