Hippocampal PDE4A Knockdown Ameliorates Alcohol-Induced Cognitive and Synaptic Impairment via the cAMP/PKA/CREB Pathway

摘要

Objective:Chronic excessive alcohol consumption leads to progressive and irreversible damage to the central nervous system,involving neuronal structural impairment,neurotransmitter dysregulation,and neuroinflammation.Among alcohol-related neurological disorders,alcoholic dementia (Al D) is one of the most severe outcomes,posing a significant threat to cognitive health in middle-aged and elderly individuals worldwide.Clinical evidence indicates that Al D patients not only exhibit core cognitive deficits such as progressive memory loss and executive dysfunction,but are also frequently experience personality changes and loss of social adaptability imposing substantial burdens on families and society.Phosphodiesterase 4 (PDE4) inhibitors have shown potential in ameliorating cognitive impairment due to their key role in regulating neural signaling.However,the clinical application of these inhibitors has been limited by strong emetic side effects mediated by the PDE4D subtype Previous studies have demonstrated that chronic alcohol exposure specifically upregulates PDE4A expression in brain tissue.However,direct experimental evidence regarding whether PDE4A represents a viable therapeutic target for Al D and its underlying mechanisms remains lacking.Methods:A stable mouse model of alcoholic disease (Al D)was established using 3-month-old 3x Tg-AD mice subjected to a free-choice,two-bottle alcohol drinking protocol (25%alcohol concentration) for 19 weeks.Behavioral tests,including the Morris water maze,novel object recognition,and Y-maze confirmed that the model recapitulated the core cognitive deficits of Al D.Pathological examinations revealed neuropathological features such as increased hippocampal Aβ deposition,synaptic disruption,elevated phosphorylation of Tau at Ser214 and Ser404,and neuronal apoptosis.To investigate the role of PDE4A,adeno-associated virus (AAV)-mediated RNA interference (RNAi) was employed to specifically knock down PDE4A expression in the hippocampus.Results:PDE4A knockdown significantly improved cognitive performance in Al D mice,as demonstrated by shortened escape latency in the Morris water maze,increased time spent in the target quadrant,higher number of platforms crossing;improved novel object recognition index;and prolonged novel arm exploration time was.At the neuropathological level,PDE4A knockdown significantly reduced Aβ deposition and decreased Tau phosphorylation at Ser214 and Ser404,and enhanced synaptic plasticity evidenced by increased expression of PSD95 and Synaptophysin,elevated dendritic branch length and number,and higher dendritic spine density.Additionally,Bax expression was downregulated while Bcl2 was upregulated,resulting in reduced neuronal apoptosis.Conclusion:This study demonstrates that targeted knockdown of PDE4A exerts strong neuroprotective effect in a mouse model of Al D.PDE4A suppression reduces Aβ accumulation,normalizes Tau hyperphosphorylation,decreases neuronal apoptosis,and ameliorates synaptic,leading to significant cognitive improvement.The protective mechanism involves activation of the c AMP/PKA signaling pathway and subsequent regulation of the CREB-BDNF neuroprotective axis.These findings highlight the critical role of the c AMP/PKA/CREB pathway in Al D and identify PDE4A as a promising therapeutic target.

关键词

alcoholic dementia / phosphodiesterase-4A / 3xTg-AD mice / cognitive deficits / synaptic damage / cAMP/PKA/CREB pathway