Department of Neurology, University of Michigan, Ann Arbor, MI, United States.
NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, United States.
Front Immunol. 2022 Sep 29;13:1012594. doi: 10.3389/fimmu.2022.1012594. eCollection 2022.
Obesity, prediabetes, and diabetes are growing in prevalence worldwide. These metabolic disorders are associated with neurodegenerative diseases, particularly Alzheimer's disease and Alzheimer's disease related dementias. Innate inflammatory signaling plays a critical role in this association, potentially the early activation of the cGAS/STING pathway. To determine acute systemic metabolic and inflammatory responses and corresponding changes in the brain, we used a high fat diet fed obese mouse model of prediabetes and cognitive impairment. We observed acute systemic changes in metabolic and inflammatory responses, with impaired glucose tolerance, insulin resistance, and alterations in peripheral immune cell populations. Central inflammatory changes included microglial activation in a pro-inflammatory environment with cGAS/STING activation. Blocking gap junctions in neuron-microglial co-cultures significantly decreased cGAS/STING activation. Collectively these studies suggest a role for early activation of the innate immune system both peripherally and centrally with potential inflammatory crosstalk between neurons and glia.
肥胖、前驱糖尿病和糖尿病在全球范围内的患病率不断上升。这些代谢紊乱与神经退行性疾病有关，特别是阿尔茨海默病和阿尔茨海默病相关痴呆症。先天炎症信号在这种关联中起着关键作用，可能是 cGAS/STING 途径的早期激活。为了确定急性全身代谢和炎症反应以及大脑相应的变化，我们使用高脂肪饮食喂养的前驱糖尿病和认知障碍肥胖小鼠模型。我们观察到代谢和炎症反应的急性全身变化，表现为葡萄糖耐量受损、胰岛素抵抗以及外周免疫细胞群的改变。中枢炎症变化包括小胶质细胞在促炎环境中的激活，伴有 cGAS/STING 的激活。在神经元-小胶质细胞共培养物中阻断缝隙连接显著降低了 cGAS/STING 的激活。这些研究表明，先天免疫系统在全身和中枢神经系统的早期激活具有重要作用，神经元和神经胶质之间可能存在炎症串扰。
