PDE8B inhibitor PF-04957325 improves cognition and reduces neuroinflammation in Aβ-induced Alzheimer's mouse models.

Effective treatments for Alzheimer's disease (AD), characterized by amyloid-β (Aβ) deposition, neuroinflammation, and cAMP/PKA/CREB pathway dysregulation, remain elusive. Current therapies often target single aspects, leaving a significant gap in addressing the multifaceted pathology. Phosphodiesterase 8B (PDE8B), an enzyme that degrades cyclic AMP (cAMP), presents a novel target. Elevating intracellular cAMP can enhance synaptic plasticity and neuronal survival, making PDE8B inhibition a promising strategy to counteract AD's complex neurodegenerative processes.

Researchers induced an AD model in mice via intracerebroventricular injection of Aβ1-42. Following induction, mice received oral administration of PF-04957325 at 0.1 mg/kg/day. Cognitive performance was assessed using the Morris water maze. Hippocampal pathology, Aβ burden, and apoptosis were evaluated via H&E, immunohistochemistry, and TUNEL assays. Inflammatory markers IL-1β and IL-6 were quantified by ELISA in hippocampal tissue and BV2 cell supernatants. Western blotting was used to measure APP, p-tau, and key pathway proteins. In vitro experiments with BV2 cells and si-PDE8B validated mechanistic findings.

Oral PF-04957325 significantly improved cognitive function in Aβ-induced AD mice. In the Morris water maze, it shortened escape latency (p < 0.01) and increased both platform crossings and target-quadrant dwell time (p < 0.01). Histologically, PF alleviated hippocampal neuronal injury, reduced Aβ burden, and decreased TUNEL-positive apoptotic cells. Molecularly, PF elevated intracellular cAMP and increased p-PKA/PKA and p-CREB/CREB ratios (p < 0.01).