Abstract
Chronic neuroinflammation characterized by microglia reactivity is one of the main underlying processes in the initiation and progression of neurodegenerative diseases such as Alzheimer’s disease. This project characterized spatial memory during healthy aging and prolonged neuroinflammation in the chronic neuroinflammatory model, glial fibrillary acidic protein-interleukin 6 (GFAP-IL6). We investigated whether chronic treatment with the natural flavonoid, apigenin, could reduce microglia activation in the hippocampus and improve spatial memory. GFAP-IL6 transgenic and wild-type-like mice were fed with apigenin-enriched or control chow from 4 months of age and tested for spatial memory function at 6 and 22 months using the Barnes maze. Brain tissue was collected at 22 months to assess microgliosis and morphology using immunohistochemistry, stereology, and 3D single cell reconstruction. GFAP-IL6 mice showed age-dependent loss of spatial memory recall compared with wild-type-like mice. Chronic apigenin treatment decreased the number of Iba-1+ microglia in the hippocampus of GFAP-IL6 mice and changed microglial morphology. Apigenin did not reverse spatial memory recall impairment in GFAP-IL6 mice at 22 months of age. GFAP-IL6 mice may represent a suitable model for age-related neurodegenerative disease. Chronic apigenin supplementation significantly reduced microglia activation, but this did not correspond with spatial memory improvement in the Barnes Maze.
Highlights
Neuroinflammation is a fundamental process underlying the initiation and progression of neurodegenerative diseases such as Alzheimer’s disease (AD)
To investigate how the accumulating effects of aging and chronic microglial activation impact on cognitive function and if cognitive decline could be ameliorated by apigenin supplementation, we performed the Barnes Maze (BM) test on apigenin and standard diet-fed WT and GFAP-IL6 mice at 6 and 22 months of age
Higher Primary Latency During Acquisition in 22 Months Old GFAP-IL6 Mice Glial fibrillary acidic protein-interleukin 6 mice exhibited a higher primary latency compared to WT controls [“genotype” F(1,34) = 15.5, p < 0.0001]; this was evident at 22 months, but not at 6 months [“age” × “genotype” F(1,34) = 6.0, p = 0.02] (Figures 1A,B)
Summary
Neuroinflammation is a fundamental process underlying the initiation and progression of neurodegenerative diseases such as Alzheimer’s disease (AD). Microglia have macrophage-like activities and contribute to the maintenance of CNS homeostasis (Bazan et al, 2012; Ginhoux et al, 2013; DiSabato et al, 2016) They can be categorized into ramified (resting), primed, reactive, and amoeboid (phagocytic), and each category shows differences in cell body morphology, branching structure and process length (Soltys et al, 2001; Stence et al, 2001; Karperien et al, 2013; Torres-Platas et al, 2014). Microglial function during aging is marked by a switch from their neuroprotective inflammatory nature which involves the production of anti-inflammatory mediators, to a proinflammatory profile in the aged brain upon activation (Sochocka et al, 2017) These features suggest that aging has a significant impact on microglial function and subsequent neurotoxicity
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