Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, GA, 30322, USA.
J Neuroinflammation. 2021 Nov 20;18(1):273. doi: 10.1186/s12974-021-02297-7.
Alzheimer's disease (AD) causes substantial medical and societal burden with no therapies ameliorating cognitive deficits. Centralized pathologies involving amyloids, neurofibrillary tangles, and neuroinflammatory pathways are being investigated to identify disease-modifying targets for AD. Cyclooxygenase-2 (COX-2) is one of the potential neuroinflammatory agents involved in AD progression. However, chronic use of COX-2 inhibitors in patients produced adverse cardiovascular effects. We asked whether inhibition of EP2 receptors, downstream of the COX-2 signaling pathway, can ameliorate neuroinflammation in AD brains in presence or absence of a secondary inflammatory stimuli.
We treated 5xFAD mice and their non-transgenic (nTg) littermates in presence or absence of lipopolysaccharide (LPS) with an EP2 antagonist (TG11-77.HCl). In cohort 1, nTg (no-hit) or 5xFAD (single-hit-genetic) mice were treated with vehicle or TG11-77.HCl for 12 weeks. In cohort 2, nTg (single-hit-environmental) and 5xFAD mice (two-hit) were administered LPS (0.5 mg/kg/week) and treated with vehicle or TG11-77.HCl for 8 weeks.
Complete blood count analysis showed that LPS induced anemia of inflammation in both groups in cohort 2. There was no adverse effect of LPS or EP2 antagonist on body weight throughout the treatment. In the neocortex isolated from the two-hit cohort of females, but not males, the elevated mRNA levels of proinflammatory mediators (IL-1β, TNF, IL-6, CCL2, EP2), glial markers (IBA1, GFAP, CD11b, S110B), and glial proteins were significantly reduced by EP2 antagonist treatment. Intriguingly, the EP2 antagonist had no effect on either of the single-hit cohorts. There was a modest increase in amyloid-plaque deposition upon EP2 antagonist treatment in the two-hit female brains, but not in the single-hit genetic female cohort.
These results reveal a potential neuroinflammatory role for EP2 in the two-hit 5xFAD mouse model. A selective EP2 antagonist reduces inflammation only in female AD mice subjected to a second inflammatory insult.
阿尔茨海默病（AD）给医疗和社会带来了巨大的负担，目前尚无治疗方法可以改善认知障碍。目前正在研究集中的病理学，包括淀粉样蛋白、神经原纤维缠结和神经炎症途径，以确定 AD 的治疗靶点。环氧化酶-2（COX-2）是参与 AD 进展的潜在神经炎症因子之一。然而，COX-2 抑制剂在患者中的长期使用会产生不良的心血管影响。我们想知道，在存在或不存在二次炎症刺激的情况下，抑制 COX-2 信号通路下游的 EP2 受体是否可以改善 AD 大脑中的神经炎症。
我们用 EP2 拮抗剂（TG11-77.HCl）治疗 5xFAD 小鼠及其非转基因（nTg）同窝仔鼠，无论是否存在脂多糖（LPS）。在队列 1 中，nTg（未命中）或 5xFAD（单基因遗传）小鼠用载体或 TG11-77.HCl 治疗 12 周。在队列 2 中，nTg（单环境打击）和 5xFAD 小鼠（双打击）每周给予 LPS（0.5mg/kg）并用载体或 TG11-77.HCl 治疗 8 周。
全血细胞计数分析表明，LPS 在队列 2 中的两组均诱导炎症性贫血。整个治疗过程中，LPS 或 EP2 拮抗剂对体重没有不良影响。在来自双打击组的雌性而非雄性的大脑皮质中，升高的促炎介质（IL-1β、TNF、IL-6、CCL2、EP2）、神经胶质标记物（IBA1、GFAP、CD11b、S110B）和神经胶质蛋白的 mRNA 水平，由 EP2 拮抗剂治疗显著降低。有趣的是，EP2 拮抗剂对单打击组均无影响。EP2 拮抗剂治疗后，双打击雌性大脑中的淀粉样斑块沉积略有增加，但单打击遗传雌性组无此现象。
这些结果揭示了 EP2 在双打击 5xFAD 小鼠模型中的潜在神经炎症作用。选择性 EP2 拮抗剂仅减少经历二次炎症打击的 AD 雌性小鼠的炎症。
