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

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 , and cyclooxygenase-2. In addition, AβO incubation upregulated the expression of PDE8 and concurrently downregulated that of brain-derived neurotrophic factor (BDNF), cAMP, p-PKA/PKA, and p-CREB/CREB in BV2 cells, all of which were reversed by PF. In vivo experiments evidenced impaired performance in the Y-maze, NOR, and MWM; these effects were reversed by PF. Similarly, PF treatment significantly attenuated microglia activation and the release of the inflammatory factors, and reversed the changes in the expression of BDNF and PDE8/cAMP/CREB signaling in AD mice. Finally, PF reduced the generation of Aβ1-42 by suppressing the expression of APP and PS1 in APP/PS1 mice.

CONCLUSIONS

PF alleviated AD-like changes in behavior and pathology through various mechanisms, including attenuating microglia-mediated neuroinflammation, upregulating the expression of BDNF, restoring synaptic dysfunction, and inhibiting Aβ generation, which appear to be involved by PDE8/cAMP/CREB signaling. These results highlight the therapeutic potential of targeting PDE8 inhibition for AD treatment.