ABSTRACT
The microtubule associated protein tau is a major component of neurofibrillary tangles in Alzheimer disease brain, however the neuropathological processes behind the formation of neurofibrillary tangles are still unclear. Previously, 14-3-3 proteins were reported to bind with tau. 14-3-3 Proteins usually bind their targets through specific serine/threonine -phosphorylated motifs. Therefore, the interaction of tau with 14-3-3 mediated by phosphorylation was investigated. In this study, we show that the phosphorylation of tau by either protein kinase A (PKA) or protein kinase B (PKB) enhances the binding of tau with 14-3-3 in vitro. The affinity between tau and 14-3-3 is increased 12- to 14-fold by phosphorylation as determined by real time surface plasmon resonance studies. Mutational analyses revealed that Ser214 is critical for the phosphorylation-mediated interaction of tau with 14-3-3. Finally, in vitro aggregation assays demonstrated that phosphorylation by PKA/PKB inhibits the formation of aggregates/filaments of tau induced by 14-3-3. As the phosphorylation at Ser214 is up-regulated in fetal brain, tau's interaction with 14-3-3 may have a significant role in the organization of the microtubule cytoskeleton in development. Also as the phosphorylation at Ser214 is up-regulated in Alzheimer's disease brain, tau's interaction with 14-3-3 might be involved in the pathology of this disease.
Subject(s)
14-3-3 Proteins/metabolism , Phosphorylation , Serine/metabolism , tau Proteins/metabolism , 14-3-3 Proteins/immunology , Animals , Antibodies/pharmacology , Cyclic AMP-Dependent Protein Kinases/metabolism , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Immunoprecipitation/methods , Phosphorylation/drug effects , Protein Binding/drug effects , Protein Binding/physiology , Proto-Oncogene Proteins c-akt/metabolism , Rats , Surface Plasmon Resonance/methods , Time Factors , tau Proteins/pharmacologyABSTRACT
Tau protein and amyloid s (Abeta), two major components of neuropathology in Alzheimer disease (AD), have been applied for establishment of more useful biomarkers and therapeutic approaches. Total tau protein in CSF is a biomarker for AD, however increased levels of total tau in CSF were also observed in other neurological disease with dementia. Phosphorylation is an important feature of tau protein and phosphorylated tau in CSF is useful to distinguish AD from other disease. Abeta has toxic effects on neuronal cells, and its mechanisms are complicated. One of mechanism of Abeta-cytotoxicity is a down-regulation of XIAP, and this effect is observed in the low concentration of Abeta. XIAP might be a therapeutic target employing compounds that increase expression of XIAP in neuronal cells.