Purpose: Aging is the most significant risk factor for neurodegenerative disorders that are typified by cognitive deficits. Our recent work utilizing BubR1 hypomorphic (BubR1H/H) mice, an accelerated aging model, has revealed that genetic inhibition of the endogenous Wnt pathway inhibitor secreted frizzled related protein 3 (sFRP3) plays a neuroprotective role. Neuroinflammation has been suggested as a pathological hallmark of age-related neurodegeneration mediating cognitive impairment. However, whether sFRP3 inhibition has a neuroprotective effect on neuroinflammatory gliosis in BubR1H/H mice is unknown. Methods: To investigate neuroprotection from aging-related neuroinflammation by sFRP3 in vivo, we generated double Bub R1H/H;sfrp3 knockout mice and performed immunohistological analysis with cell type-specific markers for astrocytes (glial fibrillary acidic protein), and microglia (ionized calcium-binding adapter molecule 1). Given that the hippocampus is a brain structure critical for learning and memory, and is uniquely affected in aging-related neurodegeneration, we evaluated morphological changes on astrocytes and microglia via confocal imaging. Results: We demonstrate that BubR1H/H mice exhibit significantly increased levels of astrogliosis and an increased trend of microglial activation in the hilus and molecular layer of the young adult hippocampus, thus suggesting that BubR1 insufficiency accelerates glial reactivity. Importantly, our results further show that genetic inhibition of sFRP3 significantly recovers the astrogliosis and microglial activation observed in BubR1H/H mice, suggesting a critical neuroprotective role for sFRP3 in age-related neuroinflammation. Conclusions Our findings suggest that sFRP3 inhibition may represent a novel therapeutic strategy for neurodegeneration.