Neuroimmune and Redox-Inflammatory Breakdown at the Prodromal Stage of Male and Female Triple-transgenic Alzheimer´s Disease Mice, Revealing Their Premature Aging

Homeostatic systems (nervous, immune, and endocrine) and their communications network are crucial for health and aging rate. The triple transgenic mice for Alzheimer´s disease (3xTg-AD) offer a valuable model to study the pathogenesis of AD, in which oxidative-inflammatory stress is involved. We previously reported behavioral and peritoneal leukocyte function alterations and oxidative-inflammatory stress in young female 3xTg-AD compared to age-matched non-transgenic (NTg) controls. However, it is not known how the deterioration of the homeostatic system interplay occurs at prodromal stages and the effects of sex. Here, we carried out an integrative analysis of the behavioral profile, splenic and thymic leukocyte functions, splen-ic oxidative-inflammatory state and plasmatic corticosterone in male and female 3xTg-AD at 4 months, compared to NTg counterparts. At this prodromal stage, char-acterized by anxiety-like behaviors and disrupted exploration, the 3xTg-AD mice ex-hibited reduced chemotaxis, natural killer activity, and lymphoproliferation—especially in the spleen. These changes were accompanied by lower anti-inflammatory and higher pro-inflammatory cytokine concentrations, and oxidative (higher oxidants and lower antioxidants) stress, indicating a breakdown of neuroimmune and redox-inflammatory homeostasis. Notably, several of these alterations displayed sex-dependent differences. These findings suggest that neuroimmune and redox-inflammatory dysfunctions emerge at the prodromal stage, preceding endocrine changes, and may act as early in-dicators of premature aging in Alzheimer’s pathology.