The number of cases of Alzheimer's disease (AD) – currently estimated to be greater than 6 million – will rapidly increase in the coming decades. As well, the total current, estimated worldwide healthcare costs associated with managing dementia is US$818 billion, according to World Alzheimer's Report 2016. Current AD treatments provide, at best, only modest and temporary symptomatic relief, failing to alter the underlying pathophysiology, which leads to the progression of the disease. Lysophosphatidic acid (LPA), a bioactive phospholipid involved in inflammation, has been associated with development of AD. Hence, the aim of this study was to investigate whether LPA might promote AD pathology through tau hyperphosphorylation and identify the putative molecular signaling mechanisms by which LPA elicits this effect. Using human SH-SY5Y cell lines differentiated with 10µm retinoic acid to achieve a neuronal phenotype, dose-dependent effects of LPA and LPA (+) atorvastatin on cell viability and dendritic morphology were determined. PrestoBlue™ cell viability assays showed LPA decreased cell viability at 5 µm and 10µm that was prevented with 1µm atorvastatin. LPA also caused neurite retraction in a time-dependent manner, which was also attenuated by atorvastatin (1µm). Exposure of SH-SY5Y cells to LPA (10µm) enhanced expression and secretion of cytokines and stimulated threonine/tyrosine phosphorylation of ERK (extracellular-signal-regulated kinase), p38 MAPK and JNK (c-Jun N-terminal kinase). These effects were reversed by the p38 MAPK inhibitor SB203580, the JNK inhibitor JNK(i) II but not by the MEK (MAPK/ERK kinase) inhibitor, PD98059. RT-PCR demonstrated the expression of LPA receptors1 and 2 in SHSY-5Y cells. Neurite retraction was accompanied by the phosphorylation of tau (Ser404 and Thr231). Immunofluorescence analysis of phospho tau (Ser202, Thr 205) was performed to validate the phosphorylation of tau by LPA. The tau phosphorylation was significantly attenuated by atorvastatin. The effects of atorvastatin were similar to the responses elicited by treatment with MAPK inhibitors, suggesting the involvement of p38MAPK pathway. Taken together, these studies provide evidence for LPA as a tau-dependent inducer of neuronal degeneration involving the p38MAPK pathway. Prevention of the LPA-induced effects are accomplished by atorvastatin, and therefore these findings open a new avenue for exploring statins as potential therapeutics for AD.