Effects of Interleukin-6 Dysregulation in a Mouse Model of Alzheimer’s Disease: Unraveling Complexity Beyond Amyloidosis

Interleukin-6 (IL-6) is a pleiotropic cytokine implicated in neuroinflammation and Alzheimer’s disease (AD) pathophysiology, but its contribution to the phenotype associated with amyloid precursor protein (APP) overexpression remains unclear. Here, we investigated the effects of systemic IL-6 deficiency in Tg2576 mice by assessing survival, physiological parameters, behavior, learning and memory, APP/amyloid-β (Aβ)-related pathology, and gliosis in young and aged male and female mice. In this specific cohort of animals, Tg2576 mice exhibited reduced survival and body weight, together with age- and sex-dependent alterations in behavioral and cognitive parameters. Notably, despite increased circulating Aβ40 and Aβ42, Aβ40 and Aβ42 were undetectable in the brain, and amyloid plaques were absent in Tg2576 mice compared with plaque-positive control mice. IL-6 deficiency partially rescued several of these phenotypes, particularly in females. Thus, the APP overexpression-associated phenotype observed here occurred in the absence of detectable cerebral amyloidosis, highlighting that APP overexpression-associated alterations can manifest independently of amyloid plaque deposition. Together, our findings underscore the complexity of AD pathogenesis and emphasize the multifaceted nature of IL-6 in both physiological and neurodegenerative processes, particularly in the context of AD.