Autotaxin⁻Lysophosphatidic Acid Signaling in Alzheimer's Disease

The brain contains various forms of lipids that are important for maintaining its structural integrity and regulating various signaling cascades. Autotaxin (ATX) is an ecto-nucleotide pyrophosphatase/phosphodiesterase-2 enzyme that hydrolyzes extracellular lysophospholipids into the lipid mediator lysophosphatidic acid (LPA). LPA is a major bioactive lipid which acts through G protein-coupled receptors (GPCRs) and plays an important role in mediating cellular signaling processes. The majority of synthesized LPA is derived from membrane phospholipids through the action of the secreted enzyme ATX. Both ATX and LPA are highly expressed in the central nervous system. Dysfunctional expression and activity of ATX with associated changes in LPA signaling have recently been implicated in the pathogenesis of Alzheimer's disease (AD). This review focuses on the current understanding of LPA signaling, with emphasis on the importance of the autotaxin⁻lysophosphatidic acid (ATX⁻LPA) pathway and its alterations in AD and a brief note on future therapeutic applications based on ATX⁻LPA signaling.