Han-Ting Zhang

Alcohol use disorder (AUD) is a major cause of cognitive impairment, yet the molecular mechanisms underlying alcoholic dementia remain unclear. Epigallocatechin gallate (EGCG), the major catechin in green tea, has shown neuroprotective potential, but its targets in alcoholic dementia are undefined. This study aimed to explore disease-associated candidate molecular markers and potential EGCG-related targets in alcoholic dementia through integrated bioinformatics, machine learning, molecular docking, and experimental analyses. Differentially expressed genes (DEGs) from GEO datasets GSE5281 and GSE62699 were subjected to functional enrichment, protein–protein interaction (PPI) network analysis, and machine learning-based feature selection. Exploratory receiver operating characteristic (ROC) analysis, immune infiltration analysis, molecular docking, and experimental assays were subsequently performed. We identified 60 overlapping DEGs enriched in synaptic signaling, postsynaptic structure, GABA-A receptor activity, and cytokine receptor activity. IL-1R1 and ID3 were identified as candidate genes associated with immune infiltration, and both were upregulated in the hippocampus of ethanol-exposed mice. These findings highlight IL1R1 and ID3 as exploratory candidate genes and provide a preliminary basis for further investigation of EGCG in the context of alcohol-associated cognitive impairment.

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Introduction: Alcohol use disorder (AUD) is a specific psychological state induced by repeated heavy drinking, and withdrawal symptoms such as anxiety are closely related to relapse after withdrawal. While neuronal damage caused by alcohol is considered a significant precipitating factor for withdrawal-induced anxiety, the underlying molecular mechanisms remain unclear. Methods: In this study, we established a mouse model of alcohol withdrawal through 3 months of chronic ethanol exposure (CEE) followed by withdrawal. Mice were treated with semaglutide (0.03 mg/kg) via intraperitoneal injection and subjected to behavioral, biochemical, and morphological analyses. Results: Our results demonstrate that the glucagon-like peptide-1 receptor (GLP-1R) agonist semaglutide alleviates anxiety-like behaviors in CEE withdrawal mice and reverses the downregulation of GLP-1R and its downstream effector CREB in the mitochondria of prefrontal cortex (PFC) neurons. Enhancing the GLP-1R/CREB pathway regulates mitochondrial quality control, including fission, fusion, and mitophagy, to maintain mitochondrial function and ameliorate synaptic impairment. Discussion: These findings suggest that activation of GLP-1R ameliorates alcohol withdrawal-induced anxiety-like behaviors by regulating neuronal mitochondrial function, providing a potential therapeutic target for AUD.