PDE4A knockdown rescues alcohol-induced cognitive impairment and synaptic dysfunction via the cAMP/PKA/CREB pathway

Alcoholic dementia (AlD) is a severe neurological disorder with no effective treatment. Development of pan-phosphodiesterase-4 (PDE4) inhibitors for clinical treatment of neurological conditions has been hampered by emetic side effects primarily mediated by PDE4D, one of the four subtypes of PDE4. Although PDE4A was shown to be upregulated by chronic alcohol exposure, its therapeutic relevance to AlD remains unclear.

A stable mouse model of AlD was established in 3-month-old 3xTg-AD mice using a free-choice two-bottle protocol (25% alcohol) for 19 weeks. Mice received either rolipram injections for 3 weeks or PDE4A knockdown for 6 weeks. Cognitive function was assessed using the Morris water maze, novel object recognition, and Y-maze tests. Hippocampal neuropathology-including Aβ deposition, synaptic integrity, Tau phosphorylation (at Ser214/Ser404), and neuronal apoptosis-was evaluated by immunofluorescence or immunohistochemistry. Changes in key proteins of the cAMP/PKA/CREB signaling pathway were analyzed by Western blotting.

This study demonstrated that selectively targeting PDE4A rescued cognitive and neuropathological deficits in a validated mouse model of AlD. Behavioral tests showed that PDE4A knockdown significantly improved spatial memory and cognition in the Morris water maze, novel object recognition, and the Y maze in the AlD mice. Pathological analysis revealed that PDE4A knockdown reduced amyloid-beta (Aβ) deposition and phosphorylated Tau levels. Furthermore, it restored synaptic integrity, as evidenced by the upregulation of PSD95 and Synaptophysin, enhanced dendritic complexity, and increased spine density, while also exerting neuroprotective effects by suppressing neuronal apoptosis in AlD mice. Mechanistically, the therapeutic benefits of PDE4A knockdown were mediated through the reactivation of the critically impaired cAMP/PKA/CREB signaling pathway, leading to elevated cAMP levels, increased PKA activity, and enhanced phosphorylation of CREB.

Our findings established PDE4A as one of the key AlD pathological drivers and identified its selective inhibition as a novel and promising therapeutic strategy for AlD, offering a viable approach to circumvent the adverse effects associated with broad-spectrum PDE4 inhibition.