NEUROINFLAMMATION AND OXIDATIVE STRESS AS EARLY DETERMINANTS OF SYNAPTIC DYSFUNCTION AND COGNITIVE IMPAIRMENT IN MOUSE MODELS OF FAMILIAL AND SPORADIC ALZHEIMER’S DISEASE

Neuroinflammation and oxidative stress are increasingly implicated as early drivers of Alzheimer’s disease (AD) pathogenesis. In particular, microglial activation and excessive reactive oxygen species production (ROS) may impair synaptic function and contribute to cognitive decline. This study examines the roles of oxidative stress, inflammatory processes, and microglial activation in preclinical familial and sporadic AD models.
We employed the triple-transgenic (3×Tg-AD) mouse model, representing early-onset familial AD, and the Herpes Simplex Virus type 1 (HSV-1) mouse model, recapitulating sporadic AD. Molecular, morphological, electrophysiological and behavioral analyses were performed. Oxidative stress markers (heme oxygenase-1, superoxide dismutase 1, 4-hydroxynonenal) and neuroinflammatory markers, including NLRP3 inflammasome expression, cytokine levels and microglia morphology were assessed. Synaptic function and cognitive performance were evaluated by hippocampal long-term potentiation and memory tasks.
Both 3×Tg-AD and HSV-1 mice exhibited similar oxidative imbalance, characterized by elevated ROS and lipid peroxidation, alongside compensatory upregulation of antioxidant enzymes HO-1 and SOD1. Neuroinflammatory markers, including NLRP3 inflammasome and key cytokines, were significantly increased. Microglia displayed a reactive phenotype, with enlarged soma, reduced branching, and higher CD68 expression. These alterations correlated with impaired synaptic plasticity and hippocampal-dependent memory deficits. Notably, the AD-like phenotype was reversed by anti-inflammatory treatment administered prior to amyloid-β and tau accumulation, whereas later intervention was ineffective.
Our findings identify oxidative stress and neuroinflammation as convergent pathogenic mechanisms in both mouse models of AD. These processes critically contribute to synaptic dysfunction and cognitive decline, supporting their relevance as potential targets for early therapeutic interventions to modify disease progression.