DETERMINING THE ROLE OF TNF-MEDIATED INFLAMMATION IN AGE-ASSOCIATED COGNITIVE CHANGES

Age-associated inflammation is a major contributor to cognitive decline, with tumour necrosis factor (TNF) identified as a key mediator. Previous studies have reported that aged male mice with whole-body genetic ablation of TNF (TNF knockout; TNFKO) exhibit improved spatial learning and memory compared to aged wild-type (WT) mice. In the central nervous system, TNF is primarily produced by activated microglia. We hypothesized that TNF-dependent changes in microglial density and morphology in the hippocampus contribute to impaired learning and memory performance in aged WT mice compared to aged TNFKO mice. We used the automated IntelliCage system to assess exploration, spatial learning, and cognitive flexibility in young (<6 months) and aged (>18 months) WT C57BL/6J and TNFKO mice. Coronal brain sections were stained for Iba1 and TMEM119 to distinguish microglia from infiltrating macrophages. Microglial density and morphology were quantified in the hippocampus. Gene expression changes associated with neuroinflammation were assessed using the NanoString Neuroinflammation Panel. Aged TNFKO male mice showed improved performance in cognitive flexibility tasks compared to aged WT mice. Preliminary analyses indicate that TNF contributes to increased microglial density without significant changes in microglial morphology. NanoString analysis revealed increased complement pathway expression under chronic TNF conditions, suggesting enhanced synaptic pruning. These findings, supported by data from the Canadian Longitudinal Study on Aging linking elevated TNF levels to poorer memory and executive function, suggest that TNF-driven microglial alterations may contribute to age-related impairments in cognitive flexibility in older adults.