Modulation of Amyloid-β Production by Leukotriene B 4 via the γ-Secretase Pathway

Abstract

Inflammatory mechanisms have been implicated in Alzheimer's disease (AD) pathogenesis, and among them, the pro-inflammatory 5-lipoxygenase (5LO) enzyme. While previous work has shown that 5LO modulates the amyloidotic phenotype of AD, the exact metabolic product responsible for this biological action remains unknown. In this study, we challenged neuronal cells with leukotriene B4 (LTB₄), a major 5LO product, and found that it increased amyloid-β formation whereby elevating the steady-state levels of the γ-secretase proteins, suggesting that LTB₄ is the mediator of the 5LO effect. Therapies that by blocking 5LO activation suppress the formation of LTB₄ or its action represent novel AD therapeutic opportunities.