The neurite retraction induced by lysophosphatidic acid increases Alzheimer's disease-like Tau phosphorylation

The bioactive phospholipid lysophosphatidic acid (LPA) causes growth cone c ollapse and neurite retraction in neuronal cells. These changes are brought about by the action of a cell surface receptor coupled to specific G prote ins that control morphology and motility through the action of a group of s mall GTPases, the Rho family of proteins. Many studies have focused on acti n reorganization modulated by Rho-GTPases, but almost no information has be en obtained concerning microtubular network reorganization after LPA-induce d neurite retraction. In the present study, we demonstrate an increase in s ite-specific Alzheimer's disease-like Talc phosphorylation during LPA-induc ed neurite retraction in differentiated SY-SH5Y human neuroblastoma cells. The phosphorylation state of Tau was inferred from its immunoreactivity wit h antibodies that recognize phosphorylation-sensitive epitopes. The effects of specific kinase inhibitors indicate that this phosphorylation is mediat ed by glycogen synthase kinase-3 (GSK-3). In support of this idea, we obser ved an increase of GSK-3 activity upon growth cone collapse. Our results ar e consistent with the hypothesis that activation of GSK-3 occurs in the Rho pathway and may represent an important link between microtubules and micro filaments dynamics during neuritogenesis and in pathological situations suc h as Alzheimer's disease.