Effects of Interleukin-6 dysregulation in a mouse model of Alzheimer’s disease: unraveling the complexity beyond amyloidosis

Interleukin-6 dysregulation has been implicated in the pathological progression of Alzheimer’s disease (AD), a leading cause of dementia in the ageing population. Here we show that chronic neuroinflammation elicited by transgenic expression of IL-6 and systemic IL-6 deficiency influences the phenotype of the Tg2576 mouse model of AD, modulating mortality, body weight, behavioral and cognitive traits, amyloidosis, and neuroinflammation. While the conventional understanding of AD pathophysiology emphasizes the central role of Aβ peptides and amyloid plaques in the development and progression the disease, the absence of amyloidosis in the brain in a specific subset of Tg2576 mice challenges this notion. This suggests that several Tg2576-related traits may manifest independently of Aβ, pointing to a potential contribution of alternative APP-related factors or pathways to the phenotypic alterations observed in Tg2576 mice. 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.