To address the possible mechanisms underlying tau-induced pathology, we determined the main tau species produced in each condition. P301S tau leads to the progressive accumulation of misfolded forms, as well as tau multimers, which correlates with the progression of motor deficits. In contrast, WT tau overexpression produces only low levels of aggregated tau. However, compared to P301S tau, the protein appeared to be more heavily phosphorylated at several specific residues, such as Ser 396, Ser 202/Thr 205, Thr 181 and Thr 231. With respect to WT tau, the 2P variant does has similar abundance of misfolded tau species. Instead, it is characterized by reduced the levels of tau phosphorylation. Consistent with its low levels of aggregation and phosphorylation, 2P tau promotes the stabilization of microtubules both in vivo and in cultures of cortical neurons exposed to vinblastine, which suggests that this form of tau is more prone to interact with microtubules.