Inflammation in the brain has emerged as a significant contributor to the neurodegenerative process in AD. TNF-alpha is one of the most prominent pro-inflammatory cytokines and plays a central role in initiating and sustaining the cytokine cascade during inflammatory responses. Inhibiting TNF-alpha ameliorates amyloid-associated pathology, prevents the progressive loss of neurons and at last improves cognitive deficits in AD animal models. The authors have previously found that genetic deletion of TNF receptor I inhibits Abeta generation through decreasing BACE1 levels and activity, implicating TNFalpha/ TNF receptor I/NF-kB signaling pathway in BACE1 regulation.
In the current study the authors chronically administrated thalidomide on human APPswedish mutation transgenic (APP23) mice from 9 months old (an onset of Abeta deposits and early stage of AD-like changes) to 12 months old. They found that, in addition of dramatic decrease in the activation of both astrocytes and microglia, thalidomide significantly reduces Abeta load and plaque formation. Furthermore, we found a significant decrease in BACE1 level and activity with long-term thalidomide application. Interestingly, these findings were not observed in the brains of 12-month-old APP23 mice with short-term treatment of thalidomide (3 days). These results suggest that chronic thalidomide administration is an alternative approach for AD prevention and therapeutics.