📋 Browse Articles

Impaired nuclear translocation of glucocorticoid receptor (GR) has been implicated in hippocampal vulnerability in Alzheimer's disease (AD), yet the molecular basis of this defect remains poorly understood. This study identified Huntingtin-associated protein 1 (Hap1) as a critical regulator of GR nuclear translocation in the hippocampus. Specifically, Hap1 expression progressively declined in the hippocampus of APP/PS1 mice with advancing age and pathological burden. Hippocampal Hap1 knockdown induced pronounced cognitive deficits and synaptic deterioration, as indicated by reduced dendritic arborization, decreased spine density, impaired long-term potentiation, and exacerbated amyloid-β deposition. Mechanistic analyses showed that Hap1 deficiency increased GR ubiquitination and proteasomal degradation and, more importantly, disrupted ligand-dependent GR translocation to the nucleus, thereby attenuating GR-dependent brain-derived neurotrophic factor transcription. In parallel, Hap1 knockdown elevated corticosterone concentration and induced depression-like behavior, consistent with hypothalamic-pituitary-adrenal axis dysregulation. Collectively, these findings establish defective GR nuclear trafficking driven by loss of Hap1 function as a key pathomechanism linking intracellular transport failure to synaptic dysfunction in AD and highlight Hap1 as a potential therapeutic target. Show less

The vital role of brain-derived neurotrophic factor (BDNF) in neuronal development, synaptic plasticity, and neuroprotection has been explored for decades. Therefore, the expression, processing, and signalling activities of this neurotrophin, which is reliant upon TrkB and p75NTR receptors, have been well characterised in both health and disease. This review summarises the latest findings on BDNF dysregulation in neuropathologies. Indeed, across diseases of both the central and peripheral nervous systems, BDNF signalling is frequently disrupted, contributing to neuronal dysfunction and degeneration. Consequently, through direct or indirect enhancement of its expression and/or function, BDNF has proved to be a promising therapeutic target across many neurological conditions. However, the complexity of its regulation and interaction with several different receptors underpins the need for further research to deepen our understanding of BDNF disruption in neuropathologies and to achieve its therapeutic potential. Show less

To date, the burden of alcohol-related seizures is increasing, with an unexplored etiological complex, and the psychopharmacological interplay remains significantly scarce. In this study, we developed an experimental approach to investigate the contrasting impact of alcohol on pentylenetetrazol-induced seizures and the effects of diosgenin, a phytosteroid agent with neuroprotective effects. After 7 days of binge alcoholism with ethanol (2 g/kg, oral gavage) in male mice, they were subjected to maximum and sub-convulsive pentylenetetrazol-induced seizures concomitantly with diosgenin (25 and 50 mg/kg, p.o.) or diazepam (3 mg/kg, p.o) treatments from days 8-14. The interaction between ethanol and pentylenetetrazol-induced seizures was investigated, along with behavioral comorbidities, hypothalamic-adrenal-pituitary-axis (HPA-axis), neurochemical and neurotrophic dysfunctions, oxidative stress, and neuroinflammation in the hippocampus, prefrontal cortex, and striatum. Ethanol-exacerbated pentylenetetrazol-induced seizure and frequency, characterized by rearing with myoclonic jerks, and clonic-tonic convulsions. It increased anxiety, depressive behavior and impaired spatial working memory, influenced by heightened alcohol preference and corticosterone levels, which were normalized by diosgenin. Concomitant ethanol administration exacerbated reductions in GABAergic-dependent glutamic acid decarboxylase and increased glutamate levels associated with pentylenetetrazol-induced seizures, alongside depletions of serotonin and brain-derived neurotrophic factor in the hippocampus, prefrontal cortex, and striatum. Among others, diosgenin, compared to ethanol-pentylenetetrazol exacerbation, reduced levels of myeloperoxidase, TNF-α, and IL-6, nitrite and malondialdehyde in the hippocampus, prefrontal cortex, and striatum while increasing IL-10 cytokine and antioxidant system (superoxide-dismutase, glutathione, and glutathione-transferase). These findings suggest that alcoholism exacerbates seizures across brain regions, involving neurochemical imbalance, HPA-axis dysfunction, oxidative stress, and neuroinflammation, which are reversible by diosgenin. Show less

Alzheimer's disease (AD) is a neurodegenerative disorder and the predominant cause of dementia, characterized by amyloid β (Aβ) plaques and tau tangles that disrupt neurons in memory-related brain regions. This study explores the therapeutic potential of santonin using integrated Show less