引言：越来越多的证据表明，包括阿尔茨海默病（AD）在内的神经退行性疾病是基因与环境相互作用的产物。免疫系统是介导这些相互作用的主要贡献者。外周免疫细胞与中枢神经系统（CNS）微血管和脑膜、血脑屏障、肠道内部的免疫细胞之间的信号传递可能在AD中起重要作用。细胞因子肿瘤坏死因子（TNF）在AD患者中升高，调节大脑和肠道屏障渗透性，由中央和外周免疫细胞产生。我们的研究小组先前报道了可溶性TNF（sTNF）如何调节细胞因子和趋化因子级联反应，从而调节5xFAD雌性小鼠外周免疫细胞进入大脑，另一项研究表明高脂高糖饮食（HFHS）会失调触发sTNF依赖性的免疫和代谢反应的信号通路，导致代谢综合征，这是AD的危险因素。我们假设sTNF是外周免疫细胞对AD类病理、代谢紊乱和饮食引起的肠道菌群失调的关键调节因子。方法：雌性5xFAD小鼠接受HFHS饮食2个月，然后在最后一个月接受XPro1595抑制sTNF或盐水肌注。我们通过多色流式细胞仪对从脑和血液中分离的细胞进行免疫细胞分析；进行代谢、免疫和炎症mRNA和蛋白标志物的生化和免疫组织化学分析、肠道微生物组和脑片电生理学分析。结果：我们展示了生物学物质XPro1595选择性抑制sTNF信号通路如何调节5xFAD小鼠HFHS饮食对外周和中枢免疫细胞结构、肠道菌群组成和长时程增强缺陷的影响。讨论：肥胖型饮食诱导5xFAD小鼠的免疫和神经功能障碍，sTNF抑制减轻了其影响。需要进行一项针对由于遗传易感性和与外周炎症共病相关联的潜在炎症风险的受试者的临床试验，以调查这些发现在临床上的适用性。版权所有 © 2023 MacPherson，Eidson，Houser，Weiss，Gollihue，Herrick，de Sousa Rodrigues，Sniffen，Weekman，Hamilton，Kelly，Oliver，Yang，Chang，Sampson，Norris和Tansey。

Introduction: Increasing evidence indicates that neurodegenerative diseases, including Alzheimer's disease (AD), are a product of gene-by-environment interplay. The immune system is a major contributor mediating these interactions. Signaling between peripheral immune cells and those within the microvasculature and meninges of the central nervous system (CNS), at the blood-brain barrier, and in the gut likely plays an important role in AD. The cytokine tumor necrosis factor (TNF) is elevated in AD patients, regulates brain and gut barrier permeability, and is produced by central and peripheral immune cells. Our group previously reported that soluble TNF (sTNF) modulates cytokine and chemokine cascades that regulate peripheral immune cell traffic to the brain in young 5xFAD female mice, and in separate studies that a diet high in fat and sugar (HFHS) dysregulates signaling pathways that trigger sTNF-dependent immune and metabolic responses that can result in metabolic syndrome, which is a risk factor for AD. We hypothesized that sTNF is a key mediator of peripheral immune cell contributions to gene-by-environment interactions to AD-like pathology, metabolic dysfunction, and diet-induced gut dysbiosis. Methods: Female 5xFAD mice were subjected to HFHS diet for 2 months and then given XPro1595 to inhibit sTNF for the last month or saline vehicle. We quantified immune cell profiles by multi-color flow cytometry on cells isolated from brain and blood; metabolic, immune, and inflammatory mRNA and protein marker biochemical and immunhistological analyses, gut microbiome, and electrophysiology in brain slices were also performed. Results: Here, we show that selective inhibition of sTNF signaling via the biologic XPro1595 modulates the effects of an HFHS diet in 5xFAD mice on peripheral and central immune profiles including CNS-associated CD8+ T cells, the composition of gut microbiota, and long-term potentiation deficits. Discussion: Obesogenic diet induces immune and neuronal dysfunction in 5xFAD mice and sTNF inhibition mitigates its effects. A clinical trial in subjects at risk for AD due to genetic predisposition and underlying inflammation associated with peripheral inflammatory co-morbidities will be needed to investigate the extent to which these findings translate to the clinic.Copyright © 2023 MacPherson, Eidson, Houser, Weiss, Gollihue, Herrick, de Sousa Rodrigues, Sniffen, Weekman, Hamilton, Kelly, Oliver, Yang, Chang, Sampson, Norris and Tansey.