Novel Role of CXCR2 in Regulation of γ-Secretase Activity

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 (A beta) 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 A beta production and treatment with antagonists or immunodepletion of CXCR2's endogenous agonists leads to A beta inhibition. Further, we found that the inhibitory effect of the antagonist of CXCR2 on A beta 40 and A beta 42 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 A beta 40 and A beta 42 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 A beta 40 and A beta 42. 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 A beta. 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.