Mitochondrial dysfunction is increasingly recognized as a key factor in Alzheimer’s disease (AD) pathogenesis, but the precise relationship between mitochondrial dynamics and proteinopathies in AD remains unclear. This study investigates the role of mitochondrial dynamics and function in the hippocampal tissue and peripheral blood mononuclear cells (PBMCs) of 5xFAD transgenic mice, as a model of AD. The levels of mitochondrial fusion proteins OPA1 and MFN2 and fission proteins DRP1 and phospho-DRP1 (S616) at 3, 6, and 9 months of age were assessed. Western blot analysis revealed significantly lower levels of OPA1 and MFN2 in the hippocampus of 6- and 9-month-old transgenic (TG) 5xFAD mice compared to controls (CTR), while DRP1 and pDRP1 levels were increased in 9-month-old TG mice. Additionally, MFN2 were decreased in the PBMCs of 9-month-old TG mice, indicating systemic mitochondrial alterations. Ultrastructural analysis of hippocampal tissues showed substantial alterations in mitochondrial morphology, including abnormalities in size and shape, a preponderance of teardrop-shaped mitochondria, and alterations in the somatic mitochondria-ER complex. Notably, mitochondria-associated ER contact sites were more distant in TG mice, suggesting functional impairments. Flow cytometric measurements demonstrated decreased mitochondrial membrane potential and mass, along with increased superoxide production, in the PBMCs of TG mice, particularly at 9 months, highlighting compromised mitochondrial function. Levels of key mitochondrial proteins including VDAC, TOM2O, and mitophagy-related protein PINK1 levels altered in both central and peripheral tissue of TG mice. These findings suggest that mitochondrial dysfunction and altered dynamics are early events in AD development in 5xFAD mice, manifesting in both central and peripheral tissues, and support the notion that mitochondrial abnormalities are an integral component of AD pathology. These insights might lead to the development of targeted therapies that modulate mitochondrial dynamics and function to mitigate AD progression.

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive synaptic dysfunction, axonal pathology, and cognitive decline, with the hippocampal circuits showing particular vulnerability during disease progression. However, early-life nutritional interventions may influence long-term synaptic resilience. In this study, we investigated the long-term effects of prenatal and lactational supplementation with choline, UMP, and fish oil in the 5XFAD mouse model. To this end, hippocampal synaptic and axonal pathology was assessed at 3, 6, and 9 months using Western blotting and immunofluorescence to measure synaptophysin, PSD-95, and neurofilament medium chain (NF-M), alongside a multidimensional behavioral battery that evaluated cognitive, affective, motor, and sensory outcomes. Results showed that early-life supplementation did not significantly improve the learning performance decline, increase nociception, or reverse changes in anxiety behavior in transgenic mice. However, it attenuated synaptic decline in transgenic animals by partially preserving synaptophysin and PSD-95 levels and reducing NF-M elevations. These molecular effects were accompanied by selective behavioral modulation, including preserved learning dynamics, altered anxiety-like behavior, and delayed nociceptive hypersensitivity, while late-stage motor impairments remained largely unaffected. Overall, prenatal and lactational supplementation produced modest, age-dependent effects on synaptic markers and partially prevented neurodegenerative progression in the 5XFAD model.