Alzheimer Disease (AD), the most common neurodegenerative disease in elderly has been recently associated with the consumption of high fat diets in which Palmitic Acid (PA) is one of the principal components. Recent studies have shown that neurons can metabolize PA through β-oxidation leading to an increase in ATP levels, decrease in NAD+ concentration and reduced Sirtuin 1 expression and activity. These processes converge on the regulation of different signaling pathways that could regulate and impact posttranslational modifications (PTMs) of tau protein. To elucidate the kinases involved in these modifications, we have analyzed the phosphorylation and acetylation of different tau phospho-epitopes mainly associated with AD such as S199/202, S214, S356, S396 and the acetylation of K280. Differentiated human neuroblastoma cells that were exposed to 200 µM PA by 1 or 24h exhibited a significant increase of tau phosphorylation mediated by mTOR-dependent GSK3β activation, and also increased K280 acetylation. These changes were associated with a significant increase in tau ubiquitination and accumulation after 24 and 48h, respectively. Interestingly, the monounsaturated fatty acid, oleic acid, blocked the PA-induced tau hyperphosphorylation. Present results provide evidence of how PA metabolism contributes to biochemical modifications that lead to tau PTMs similar to those that occurred in AD.