Abstract / Summary
Neuroinflammation is a central contributor to Alzheimer’s disease (AD) progression, with tumor necrosis factor alpha (TNF-α) playing a key regulatory role as a master pro-inflammatory cytokine. While therapies inhibiting total TNF-α have produced inconsistent results and adverse effects, selective activation of TNF receptor 2 (TNFR2) has emerged as a promising strategy in AD due to its association with neuroprotection. Even though TNFR2 agonism has shown beneficial effects in amyloid-based AD mouse/rodent models, its impact on tau pathology and potential sex-dependent effects in AD remain unknown. In this study, we investigated whether long-term TNFR2 agonist treatment improves cognition, neuropathology, and immune responses in male and female 3xTg-AD mice, a model that develops both amyloid-β and tau pathology. Mice received systemic TNFR2 agonist treatment or PBS control for 12 weeks, followed by behavioral testing, immunohistochemistry, and flow cytometry to assess cognition, neuropathology, glial responses, neuronal integrity, and peripheral immune changes. TNFR2 agonist treatment reduced hippocampal total tau levels and showed a parallel trend toward lower phosphorylated tau in female mice, together with a trend toward improved spatial learning, but had no comparable effects at the hippocampal levels in males. Aβ plaque burden and BACE1 expression were unchanged. Moreover, TNFR2 agonism increased microglial coverage and plaque-associated phagocytic microglial activity in females, whereas males showed a more homeostatic glial profile and increased neuronal preservation following treatment. Finally, treatment expanded circulating regulatory T cells and altered peripheral T-cell responses in both sexes. Our findings demonstrate that TNFR2 activation shows distinct neuropathological, neuroinflammatory, peripheral, and cognitive effects in male and female 3xTg-AD mice, which likely reflect both differences in underlying pathology and treatment responsiveness. These results further highlight the importance of immune-based therapeutic strategies and the consideration of sex in the development of AD treatments, although additional mechanistic and longitudinal studies are needed to better define the pathways underlying the observed effects.