The Cellular Distribution and Ser262 Phosphorylation of Tau Protein Are Regulated by BDNF In Vitro

The brain-enriched microtubule-associated protein tau, a critical regulator of cytoskeletal dynamics, forms insoluble aggregates in a number of neurodegenerative diseases termed tauopathies, including Alzheimer's disease (AD). Hyperphosphorylation of tau protein is an important mechanism for aggregation, so many studies on the pathogenesis of AD and other tauopathies have focused on regulation of tau phosphorylation by kinases and phosphatases. Less studied are mechanisms of tau transcriptional and post-transcriptional regulation by extracellular signals such as BDNF and how such changes alter neuronal function. Previously, we reported that tau is required for morphological plasticity induced by BDNF. Here, we further explore tau modification during BDNF-induced changes in neuronal cell morphology. In undifferentiated SH-SY5Y cells lacking neurites, tau formed a sphere within the soma as revealed by immunocytochemistry. In contrast, tau was enriched in the neurites and sparse in the soma of SH-SY5Y cells induced to differentiate by retinoic acid (RA). Treatment with RA also increased total tau protein levels but decreased expression of tau phosphorylated at Ser262 as determined by Western blot. Both effects were further enhanced by subsequent BDNF treatment. Upregulation of tau protein and downregulation of p-Ser262 tau were correlated with total neurite length (R = .94 and R = -.98, respectively). When primary E18 hippocampal neurons were treated with nocodazole, a blocker of microtubule polymerization, nascent neurites were lost and tau shifted to the soma. This process of retrograde tau movement away from neurites was reversed by BDNF. These results indicate that tau is redistributed to neurites and dephosphorylated during RA- and BDNF-mediated differentiation.