Effects of roflumilast on learning and memory and related mechanisms in 3×Tg-AD mice

AimThis study aimed to evaluate the potential ameliorative effects of the phosphodiesterase 4 (PDE4) inhibitor roflumilast (Rof) on cognitive function in the 3×Tg-AD mouse model of Alzheimer′s disease (AD), while also exploring the underlying mechanisms.MethodsThirty ten-month-old 3×Tg-AD mice were randomly assigned to one of four groups: the model group, a high-dose Rof group (5 mg·kg-1), a low-dose Rof group(1 mg·kg-1), and a wild-type control group. All groups received oral gavage administration for 30 consecutive days. Behavioral assessments, histopathological evaluations, and molecular analyses were conducted to assess the effects of Rof on cognitive function, amyloid-beta (Aβ) deposition, Tau phosphorylation, the PDE4/cAMP/CREB signaling pathway, and apoptosis-related proteins.ResultsWater maze and passive avoidance tests revealed a significant decline in cognitive function in the model group compared to the control group, whereas Rof treatment significantly improved cognitive performance (PPPPPPPConclusionRof effectively reversed cognitive dysfunction and pathological damage in 3×Tg-AD mice, demonstrating its therapeutic potential for Alzheimer′s disease. These effects may be attributed to the modulation of the PDE4/cAMP/CREB signaling pathway. PDE4 inhibitors show promise as potential treatments for AD.