Differential Impact of Ovariectomy on Immune and Antioxidant Defenses in Wild- type and triple transgenic Alzheimer´s disease (3xTg-AD) mice: Protective role of voluntary exercise

Abstract Estrogen deprivation induced by ovariectomy—an established model of menopause in female rodents—accelerates aging processes, including immune dysfunction and alterations in redox homeostasis. In triple‑transgenic Alzheimer’s disease mice (3xTg‑AD), which develop premature peripheral immunosenescence and an oxidative–inflammatory imbalance from an early age, the specific impact of ovariectomy on immune function and antioxidant state remains unclear. Using 9‑month‑old animals, we evaluated multiple leukocyte functions together with antioxidant parameters in the spleen and thymus of ovariectomized 3xTg‑AD and non‑transgenic (NTg) females, their sham-operated counterparts, and age-matched males. Additionally, to assess the protective potential of physical activity, groups of NTg and 3xTg‑AD females underwent three months of voluntary wheel running prior to ovariectomy. The results show that ovariectomized NTg females displayed marked impairments in leukocyte functions and antioxidant capacity, reaching values comparable to those of males and sham 3xTg‑AD mice. In contrast, ovariectomy in 3xTg‑AD females selectively reduced glutathione concentrations without inducing further immune deterioration. Voluntary exercise improved leukocyte performance and antioxidant defenses in both 3xTg‑AD and NTg ovariectomized mice, particularly in the latter. These findings indicate that estrogen loss accelerates immunosenescence in NTg females whereas its impact in 3xTg‑AD mice is primarily restricted to antioxidant capacity due to their pre-existing premature immune aging. Moreover, voluntary physical activity emerges as an effective strategy to counteract both immune and redox decline associated with estrogen loss, even in the presence of Alzheimer´s disease pathology.