Loss of NF-?B p50 function synergistically augments microglial priming in the middle-aged brain

Background While NF-?B p50 function is impaired in central nervous system disease, aging in non-CNS tissues, and response to reactive oxygen species, the role of NF-?B p50 in aging-associated microglial pro-inflammatory priming is poorly understood. Methods Male NF-?B p50.sup.+/+ and NF-?B p50.sup.-/- mice at three different ages (1.5-3.0 month old, 8.0-11.0 month old, and 16.0-18.0 month old) were treated with LPS (5 mg/kg, IP) to trigger peripheral inflammation, where circulating cytokines, neuroinflammation, microglia morphology, and NF-?B p50/p65 function in brain tissue were determined 3 h later. Results Peripheral LPS injection in 9-month-old C57BL/6 mice resulted in lower NF-?B p50 DNA binding of nuclear extracts from the whole brain, when compared to 3-week-old C57BL/6 mice, revealing differences in LPS-induced NF-?B p50 activity in the brain across the mouse lifespan. To examine the consequences of loss NF-?B p50 function with aging, NF-?B p50.sup.+/+ and NF-?B p50.sup.-/- mice of three different age groups (1.5-3.0 month old, 8.0-11.0 month old, and 16.0-18.0 month old) were injected with LPS (5 mg/kg, IP). NF-?B p50.sup.-/- mice showed markedly elevated circulating, midbrain, and microglial TNF[alpha] when compared to NF-?B p50.sup.+/+ mice at all ages. Notably, the 16.0-18.0-month-old (middle aged) NF-?B p50.sup.-/- mice exhibited synergistically augmented LPS-induced serum and midbrain TNF[alpha] when compared to the younger (1.5-3.0 month old, young adult) NF-?B p50.sup.-/- mice. The 16.0-18.0-month-old LPS-treated NF-?B p50.sup.-/- mice also had the highest midbrain IL-1[beta] expression, largest number of microglia with changes in morphology, and greatest elevation of pro-inflammatory factors in isolated adult microglia. Interestingly, aging NF-?B p50.sup.-/- mice exhibited decreased brain NF-?B p65 expression and activity. Conclusions These findings support that loss of NF-?B p50 function and aging in middle-aged mice may interact to excessively augment peripheral/microglial pro-inflammatory responses and point to a novel neuroinflammation signaling mechanism independent the NF-?B p50/p65 transcription factor in this process. Keywords: Microglia, Aging, NF-?B, Priming