| Abstract | Alzheimer's Disease (AD) is the sixth leading cause of death in the United States, and it is the only leading cause of death that cannot be prevented, cured, or slowed. This form of dementia is characterized by amyloid-beta (Aß) senile plaques and neurofibrillary tangles which have been shown to contribute to neuro-inflammation, cell death, and the disruption of cell signaling. These pathologies are likely to blame for the cognitive deficiencies observed in AD patients. Microglial cells, the immune cells of the brain, may be attributing to the exacerbation of some of these pathologies. Microglia are plastic cells that respond accordingly to their environment and can be swayed to become activated toward the M1, proinflammatory, or the M2, anti-inflammatory, phenotype. In AD, microglia are heavily polarized toward the M1 phenotype as they are activated by Aß, dying neurons, and hyper-phosphorylated tau. Chronic inflammation, that is brought about by constantly activated M1 microglia, can lead to an increase in Aß production and worsening of AD pathology. In this study we explored the use of a drug called rolipram (ROL), a phosphodiesterase inhibitor known to have anti-inflammatory and cognitive-enhancing effects, to induce the transition of microglia from a pro-inflammatory state towards an anti-inflammatory state. We found that ROL blunts TNF-a production when it is administered to LPS-activated microglia. Furthermore, LPS-induced TNF-a production is blocked when ROL is applied prior to LPS exposure. ROL's protective effect is not due to up-regulation of the antiinflammatory mediator, Nurr1, but could possibly be attributed to a negative feedback loop with several intermediates playing a role. We also studied ROL's effects in an inflammation-induced AD model. Inability to replicate this model, and difficulty in finding a dose that did not make mice feel ill, prevented us from making conclusions about ROL's neuro-protective, cognitive enhancing, and antiinflammatory effects in this model. More research must be done to determine a proper dose and injection schedule for ROL in this model. ROL's use as a cognitive enhancing drug is promising, as several studies have shown enhanced cognitive function in ROL-treated mice with extremely low effective doses. However, it is unlikely that ROL would be used for its anti-inflammatory effects as this requires a much higher dose. Other anti-inflammatory drugs should be investigated that mimic the effects of ROL without the associated adverse side effects. |
