Alzheimer's disease (AD) is an age-related neurodegenerative disease, which characterized by deposition of amyloid-β (Aβ) plaques, neurofibrillary tangles, neuronal loss, and accompanied by neuroinflammation. Neuroinflammatory processes are well acknowledged to contribute to the progression of AD pathology. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Recently, studies show that H3R are highly expressed not only in neurons but also in microglia and astrocytes. H3R antagonist has been reported to have anti-inflammatory efficacy. However, whether inhibition of H3R is responsible for the anti-neuroinflammation in glial cells and neuroprotection on APPswe, PSEN1dE9 (APP/PS1 Tg) mice remain unclear. In this study, we found that inhibition of H3R by thioperamide reduced the gliosis and induced a phenotypical switch from A1 to A2 in astrocytes, and ultimately attenuated neuroinflammation in APP/PS1 Tg mice. Additionally, thioperamide rescued the decrease of cyclic AMP response element-binding protein (CREB) phosphorylation and suppressed the phosphorylated P65 nuclear factor kappa B (p-P65 NF-κB) in APP/PS1 Tg mice. H89, an inhibitor of CREB signaling, abolished these effects of thioperamide to suppress gliosis and proinflammatory cytokine release. Lastly, thioperamide alleviated the deposition of amyloid-β (Aβ) and cognitive dysfunction in APP/PS1 mice, which were both reversed by administration of H89. Taken together, these results suggested the H3R antagonist thioperamide improved cognitive impairment in APP/PS1 Tg mice via modulation of the CREB-mediated gliosis and inflammation inhibiting, which contributed to Aβ clearance. This study uncovered a novel mechanism involving inflammatory regulating behind the therapeutic effect of thioperamide in AD.

阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，其特征是淀粉样蛋白β（Aβ）斑块沉积、神经原纤维缠结、神经元丢失，并伴有神经炎症。众所周知，神经炎症过程有助于 AD 病理学的进展。组胺 H3 受体 (H3R) 是一种突触前自身受体，通过负反馈方式。最近，研究表明 H3R 不仅在神经元中高度表达，而且在小胶质细胞和星形胶质细胞中也高度表达。据报道，H3R 拮抗剂具有抗炎功效。然而，H3R 的抑​​制是否负责神经胶质细胞的抗神经炎症和对 APPswe、PSEN1dE9 (APP/PS1 Tg) 小鼠的神经保护作用仍不清楚。在这项研究中，我们发现硫哌酰胺对 H3R 的抑​​制减少了神经胶质增生并诱导了星形胶质细胞从 A1 到 A2 的表型转换，并最终减轻了 APP/PS1 Tg 小鼠的神经炎症。此外，硫哌酰胺在 APP/PS1 Tg 小鼠中挽救了环 AMP 反应元件结合蛋白 (CREB) 磷酸化的减少并抑制了磷酸化的 P65 核因子 kappa B (p-P65 NF-κB)。H89，一种 CREB ​​信号抑制剂，消除了硫哌酰胺抑制神经胶质增生和促炎细胞因子释放的这些作用。最后，硫哌酰胺减轻了 APP/PS1 小鼠中淀粉样蛋白-β (Aβ) 的沉积和认知功能障碍，这两种情况都可以通过施用 H89 来逆转。总之，这些结果表明 H3R 拮抗剂硫哌酰胺改善了 APP/PS1 Tg 小鼠的认知障碍通过调节 CREB ​​介导的神经胶质增生和炎症抑制，这有助于 Aβ 清除。该研究揭示了硫哌酰胺对 AD 治疗效果背后的炎症调节新机制。