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Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, synaptic dysfunction, and mitochondrial abnormalities. Mitochondrial dynamics, especially the balance between fusion and fission processes regulated by proteins like mitofusin 2 (Mfn2) and dynamin-related protein 1 (Drp1), play critical roles in neuronal health. However, the relationship between mitochondrial dynamics and synaptic integrity, and cognitive deficits remains incompletely understood. This study aimed to investigate the alterations in Mfn2 and Drp1 expression and their association with synaptic protein levels and also behavioral outcomes in a rat model of AD. Thirty adult male Wistar rats were randomly assigned to control and AD groups. AD was induced through bilateral hippocampal injection of Aβ1-42. Behavioral assessments including the Morris Water Maze, Novel Object Recognition, and Y-maze were conducted to evaluate spatial learning and memory. On day 21 post-induction, gene expression of Drp1, Mfn2, PSD-95, synaptophysin, BDNF, Bax, and Bcl2 in the hippocampus and cortex was measured using real-time PCR. Oxidative stress markers (MDA, SOD, CAT) and inflammatory cytokines (NF-κB, IL-1β) were evaluated in serum using ELISA kits. Results showed significant downregulation of Mfn2 and synaptic proteins, with increased Drp1 and Bax expression in AD rats. These molecular changes were accompanied with increase of oxidative and inflammatory markers and altered cognitive performance. In conclusion, the findings suggest that disrupted mitochondrial dynamics contribute to synaptic loss and cognitive decline in AD. Targeting mitochondrial function and neuroinflammation may represent potential therapeutic targets for AD management. Show less

Gestational intermittent hypoxia (GIH), which serves as a model for obstructive sleep apnea (OSA), is associated with adverse maternal and neonatal outcomes, especially cognitive impairments in offspring. Growing evidence supports that the anti-inflammatory actions of melatonin significantly influence the peripartum environment and contribute to the mitigation of neurodegeneration. However, the full impact of GIH on offspring cognition and the molecular mechanisms by which melatonin modulates these effects remain uncertain. Thus, in this study, we explored the neurobiological changes in GIH-exposed offspring and the mechanism underlying maternal melatonin supplementation in preventing these alterations using a murine model. C57BL/6J mice were exposed to GIH between gestational Days 15 and 21. Concurrently, dams received either vehicle or melatonin. The Morris water maze test was employed to evaluate offspring cognitive function, after which the offspring were euthanized at 2 months of age. The hippocampal levels of glial markers (ionized calcium-binding adapter molecule 1 [Iba-1], glial fibrillary acidic protein [GFAP]), NOD-like receptor thermal protein domain-associated protein 3 [NLRP3], nuclear factor-kappa B [NF-κB], tight-junction proteins (zonula occludens-1 [ZO-1], occludin), and synaptic plasticity-related proteins (brain-derived neurotrophic factor [BDNF], tropomyosin receptor kinase B [TrkB], postsynaptic density protein 95 [PSD-95], synaptophysin [SYN]) were quantified by enzyme-linked immunosorbent assay and western blot. Maternal melatonin supplementation significantly attenuated learning and memory impairments, reduced the protein levels of Iba-1 and GFAP by suppressing NLRP3/NF-κB signaling, and elevated those of ZO-1, occludin, BDNF, TrkB, PSD-95, and SYN. Additionally, melatonin mitigated inflammatory responses, glial cell activation, blood-brain barrier (BBB) leakage, and synaptic dysfunction induced by GIH in mice. Our results demonstrated that GIH-exposed mice exhibit cognitive deficits, alongside neuroinflammatory responses, leading to inflammasome activation, glial reactivity, BBB breakdown, and synaptic deficits. However, melatonin exerted significant protective effects against these deleterious effects. Show less