Stress can elicit glucocorticoid release to promote coping mechanisms and influence learning and memory performance. Individual memory performance varies in response to stress, and the underlying mechanism is not clear yet. Peroxiredoxin 6 (PRDX6) is a multifunctional enzyme participating in both physiological and pathological conditions. Several studies have demonstrated the correlation between PRDX6 expression level and stress-related disorders. Our recent finding indicates that lack of the Prdx6 gene leads to enhanced fear memory. However, it is unknown whether PRDX6 is involved in changes in anxiety response and memory performance upon stress. The present study reveals that hippocampal PRDX6 level is downregulated 30 min after acute immobilization stress (AIS) and trace fear conditioning (TFC). In human retinal pigment epithelium (ARPE-19) cells, the PRDX6 expression level decreases after being treated with stress hormone corticosterone. Lack of PRDX6 caused elevated basal H₂O₂ levels in the hippocampus, basolateral amygdala, and medial prefrontal cortex, brain regions involved in anxiety response and fear memory formation. Additionally, this H₂O₂ level was still high in the medial prefrontal cortex of the knockout mice under AIS. Anxiety behavior of Prdx6^−/− mice was enhanced after immobilization for 30 min. After exposure to AIS before a contextual test, Prdx6^−/− mice displayed a contextual fear memory deficit. Our results showed that the memory performance of Prdx6^−/− mice was impaired when responding to AIS, accompanied by dysregulated H₂O₂ levels. The present study helps better understand the function of PRDX6 in memory performance after acute stress.

Introduction: Curcumin is widely recognized for its anti-neurodegenerative properties. However, its clinical utility is hindered by poor aqueous solubility and low bioavailability. To address these limitations, Curcumin-loaded Solid Self-Emulsifying Drug Delivery Systems (C-SSEDDS) have been formulated to improve pharmacokinetics and neuronal targeting. Despite these advancements, the molecular mechanisms underlying curcumin in Alzheimer’s Disease (AD)-related neuronal senescence remain poorly understood. Therefore, this study provides novel molecular insights into the therapeutic potential of C-SSEDDS for targeting neuronal senescence- like features in the AD context. materials and methods: An in vitro neuronal aging model was established by exposing SK-N-SH cells to Aβ25-35 for 24 hours, inducing a 20-30 Methods: An in vitro model of neuronal senescence-like features was established by exposing SK-N-SH cells to 0.075 μM Aβ25-35 for 24 hours, resulting in a 20-30% decline in cell viability. Subsequently, cells were post-treated with C-SSEDDS at optimized non-toxic concentrations (0.1, 1, and 10 μg/mL curcumin equivalent) and 10 μg/mL commercial curcumin for 24, 48, and 72 hours in Aβ25-35-free media. The study comprehensively assessed cell viability, morphological alterations, and key biomarkers associated with neuronal senescence-like features, including senescence- associated beta-galactosidase (SA-β-gal) positive cells, Reactive Oxygen Species (ROS) levels, NLRP3, Sirt-1, and synaptophysin expression. results: C-SSEDDS post-treatment significantly improved cell viability, reduced apoptotic cells, and decreased SA-β-gal positive cells compared to the untreated aging neuron and curcumin post-treatment (p < 0.01). It also effectively decreased intracellular ROS and NLRP3 levels (p < 0.01), and markedly upregulated Sirt-1 and synaptophysin [removed]p < 0.01). Notably, C-SSEDDS demonstrated antioxidant properties comparable to N-acetylcysteine (NAC), a recognized standard in antioxidant therapy. Results: C-SSEDDS post-treatment significantly improved cell viability, reduced apoptotic cells, and decreased SA-β-gal positive cells in Aβ25-35-induced senescence-like SK-N-SH cells compared to the untreated Aβ25-35 group. It also effectively decreased intracellular ROS level and NLRP3 expression, and markedly upregulated Sirt-1 and synaptophysin expression. Notably, CSSEDDS demonstrated therapeutic efficacy superior to commercial curcumin and comparable to N-acetylcysteine (NAC). Discussion: In SK-N-SH cells exhibiting senescence-like features, the C-SSEDDS formulation effectively counteracts Aβ25-35-induced damage. It mitigates key drivers of cellular stress, including oxidative stress, inflammation-related markers, and apoptosis, while also enhancing Sirt-1 activity and promoting synaptic plasticity. Conclusion: C-SSEDDS demonstrates significant potential as a promising therapeutic strategy against Aβ25-35 -induced neuronal stress and senescence-like changes in AD.