Modulation of Amyloid-β Production by Leukotriene B4 via the γ-Secretase Pathway

• DOI: 10.3233/jad-131223
• Publication Date: 2018-06-04T16:10:41Z
• Authors: Yash B. Joshi; Antonio Di Meco; Domenico Praticó
• Keywords: Amyloid beta-Peptides; Membrane Glycoproteins; Membrane Proteins; Transfection; Leukotriene B4; Peptide Fragments; 3. Good health; Gene Expression Regulation, Neoplastic; Amyloid beta-Protein Precursor; Mice; Neuroblastoma; 03 medical and health sciences; 0302 clinical medicine; Cell Line, Tumor; Mutation; Animals; Humans; Amyloid Precursor Protein Secretases

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.