Alzheimer's disease (AD) is a progressive chronic disorder that leads to cognitive decline. Several studies have associated up-regulation of some of the chemokines and/or their receptors with altered APP processing leading to increased production of beta-amyloid protein (Abeta) and AD pathological changes. However, there is no direct evidence to date to determine whether the altered processing of APP results in up-regulation of these receptors or whether the up-regulation of the chemokine receptors causes modulated processing of APP. In the current study, we demonstrate that treatment of the chemokine receptor CXCR2 with agonists leads to enhancement of Abeta production and treatment with antagonists or immunodepletion of CXCR2's endogenous agonists leads to Abeta inhibition. Further, we found that the inhibitory effect of the antagonist of CXCR2 on Abeta40 and Abeta42 is mediated via gamma-secretase, specifically through reduction in expression of presenilin (PS), one of the gamma-secretase components. Also, in vivo chronic treatment with a CXCR2 antagonist blocked Abeta40 and Abeta42 production. Using small interfering RNAs for CXCR2, we further showed that knockdown of CXCR2 in vitro accumulates gamma-secretase substrates C99 and C83 with reduced production of both Abeta40 and Abeta42. Taken together, these findings strongly suggest for the first time that up-regulation of the CXCR2 receptor can be the driving force in increased production of Abeta. Our findings unravel new mechanisms involving the CXCR2 receptor in the pathogenesis of AD and pose it as a potential target for developing novel therapeutics for intervention in this disease. Also, we propose here a new chemical series of interest that can serve as a prototype for drug development.