Cognitive improvement effects of PF-04957325, a phosphodiesterase-8 inhibitor, in mouse models of Alzheimer’s disease via modulating neuroinflammation

作者：Tian-yang Guo, Meng Zhang, Yu-li Lv, Nianzhuang Qiu, Ruimin Chen, Fang‐fang Zhang, Wei Chen, Feng Zhang, Yongfeng Gao, Xiaodan Wang, Xuehui Zhang, Meihua Chen, Han‐Ting Zhang, Hao Wang · 发表于：The International Journal of Neuropsychopharmacology · 年份：2025 · DOI：10.1093/ijnp/pyaf028 · 被引用次数：8 · 研究领域：Phosphodiesterase function and regulation、Adenosine and Purinergic Signaling、Neuroinflammation and Neurodegeneration Mechanisms

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory deficit and has emerged as a growing global health concern. Phosphodiesterase-8 (PDE8) is a cyclic adenosine monophosphate (cAMP)-specific hydrolase and its correlation with AD pathogenesis remains underexplored. Here, the effects and mechanisms of PF-04957325 (denoted as PF), a PDE8 inhibitor, were investigated in reversing AD both in vitro and in vivo. METHODS: Briefly, BV2 cells were incubated with amyloid-β oligomers (AβO) to construct an AD cell model. Then, 2-month-old male C57BL/6J mice injected with AβO into the hippocampus and 10-month-old male amyloid precursor protein/presenilin-1 (APP/PS1) mice were used to construct AD animal models. Cells and mice were treated with PF to observe the effects of PDE8 on behavior and pathology related to AD. The Y-maze, novel object recognition (NOR), and Morris water maze (MWM) were performed to investigate cognitive function in mice. Western blot and immunofluorescence staining were used to identify the microglial activation state. Lastly, Western blot and ELISA were conducted to determine the levels of inflammatory factors and the proteins of PDE8/cAMP/CREB signaling. RESULTS: PF-04957325 pretreatment reversed the conversation of proinflammatory microglia in BV2 cells induced by AβO, while also suppressing the levels of inflammatory factors, including interleukin-1β, interleukin-6, tumor necrosis factor-α, inducible nitric oxide synthase ...