Linking Alterations in Tau Phosphorylation and Cleavage during Neuronal Apoptosis

Abstract

Neurofibrillary tangles (NFTs) are classic lesions of Alzheimer's disease. NFTs are bundles of abnormally phosphorylated tau, the paired helical filaments. The initiating mechanisms of NFTs and their role in neuronal loss are still unknown. Accumulating evidence supports a role for the activation of proteolytic enzymes, caspases, in neuronal death observed in brains of patients with Alzheimer's disease. Alterations in tau phosphorylation and tau cleavage by caspases have been previously reported in neuronal apoptosis. However, the links between the alterations in tau phosphorylation and its proteolytic cleavage have not yet been documented. Here, we show that, during staurosporine-induced neuronal apoptosis, tau first undergoes transient hyperphosphorylation, which is followed by dephosphorylation and cleavage. This cleavage generated a 10-kDa fragment in addition to the 17-and 50-kDa tau fragments previously reported. Prior tau dephosphorylation by a glycogen synthase kinase-3␤ inhibitor, lithium, enhanced tau cleavage and sensitized neurons to staurosporine-induced apoptosis. Caspase inhibition prevented tau cleavage without reversing changes in tau phosphorylation linked to apoptosis. Furthermore, the microtubule depolymerizing agent, colchicine, induced tau dephosphorylation and caspase-independent tau cleavage and degradation. Both phenomena were blocked by inhibiting protein phosphatase 2A (PP2A) by okadaic acid. These experiments indicate that tau dephosphorylation precedes and is required for its cleavage and degradation. We propose that the absence of cleavage and degradation of hyperphosphorylated tau (due to PP2A inhibition) may lead to its accumulation in degenerating neurons. This mechanism may contribute to the aggregation of hyperphosphorylated tau into paired helical filaments in Alzheimer's disease where reduced PP2A activity has been reported.

Phosphorylation of tau antagonizes apoptosis by stabilizing β-catenin, a mechanism involved in Alzheimer's neurodegeneration

“…In both cases, the presence of tau filaments did not correlate directly with the death of individual neurons. We also observed that dephosphorylated tau at the Tau-1 epitope was colabeled with apoptotic markers (data not shown), which supports a previous report that dephosphorylation of tau renders the cells more vulnerable to apoptosis (30). Although a proapoptotic effect of tau pseudophosphorylation was also reported (31), we conceive that the antiapoptotic function of tau requires its phosphorylation.…”

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

“…In cultured cortical neurons, lithium was found to down-regulate tau transcription (Rametti et al, 2008). In the rat brain, lithium treatment not only increased PP2A activity (Tsuji et al, 2003), but also decreased tau phosphorylation, which in turn, facilitated tau destruction (Rametti et al, 2004). Finally, the fact that blockade of PP2A activity in cultured neurons reversed lithium-induced down-regulation of total tau proteins mediated by GSK-3b inhibition (Martin et al, 2009) suggests that PP2A is involved in lithium's action.…”

“…It has been reported that the activity of PP2A is reduced in the brain of individuals with AD (Trojanowski and Lee, 1995). PP2A inhibition prevented tau dephosphorylation, a process that precedes and is required for tau cleavage and degradation (Rametti et al, 2004). In cultured cortical neurons, lithium was found to down-regulate tau transcription (Rametti et al, 2008).…”

Study of the stress proteins secreted byLeishmania donovaniafter treatment with edelfosine, mitelfosine and ilmofosine, and morphological alterations analyzed by electronic microscopy

“…After the treatment with ALPs, promastigotes synthesized specifically certain proteins, in particular protein bands of 17 and 12 kDa. Rametti et al (2004) show that during staurosporineinduced neuronal apoptosis, tau protein first underwent transient hyperphosphorylation which was followed by dephosphorylation and cleavage. This cleavage generates 10 kDa protein fragment in addition to those of 17 kDa and 50 kDa.…”