The regulation of tau phosphorylation by PCTAIRE 3: implications for the pathogenesis of Alzheimer's disease.
ABSTRACT In the course of Alzheimer's disease, phosphorylated tau aggregates to form paired helical filaments, highly ordered filamentous structures that accumulate within neurons and contribute to the formation of neurofibrillary tangles. This study examines the role of PCTAIRE 3, a cdc2 family protein kinase, within this disease process. We report an elevation in the protein levels of PCTAIRE 3 in the temporal cortex of AD relative to control brains. Analysis of paired helical filaments prepared from AD brain tissue indicates that PCTAIRE 3 is concentrated within this pathological material. Overexpression of PCTAIRE 3 in cell culture suggests that the protein acts indirectly to stimulate phosphorylation at the pT231 and pS235 sites on tau, residues that are modified early in the process of AD pathogenesis. The resurgence of cell cycle proteins is an important mechanism in Alzheimer's disease (AD), and we propose that PCTAIRE 3 is a PHF-associated kinase that modulates tau phosphorylation.
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ABSTRACT: Polarized trafficking of synaptic proteins to axons and dendrites is crucial to neuronal function. Through forward genetic analysis in C. elegans, we identified a cyclin (CYY-1) and a cyclin-dependent Pctaire kinase (PCT-1) necessary for targeting presynaptic components to the axon. Another cyclin-dependent kinase, CDK-5, and its activator p35, act in parallel to and partially redundantly with the CYY-1/PCT-1 pathway. Synaptic vesicles and active zone proteins mostly mislocalize to dendrites in animals defective for both PCT-1 and CDK-5 pathways. Unlike the kinesin-3 motor, unc-104/Kif1a mutant, cyy-1 cdk-5 double mutants have no reduction in anterogradely moving synaptic vesicle precursors (SVPs) as observed by dynamic imaging. Instead, the number of retrogradely moving SVPs is dramatically increased. Furthermore, this mislocalization defect is suppressed by disrupting the retrograde motor, the cytoplasmic dynein complex. Thus, PCT-1 and CDK-5 pathways direct polarized trafficking of presynaptic components by inhibiting dynein-mediated retrograde transport and setting the balance between anterograde and retrograde motors.Cell 05/2010; 141(5):846-58. DOI:10.1016/j.cell.2010.04.011 · 33.12 Impact Factor
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ABSTRACT: According to Traditional Chinese Medicine, Alzheimer's disease (AD) is regarded as senile dementia, and the etiopathogenesis lies in kidney deficiency during aging. Dipsacus asper Wall (DAW), a well-known traditional Chinese medicine for enhancing kidney activity, may possess the therapeutic effects against AD. Our objectives were to investigate the protective effects of DAW against the amyloid-beta peptide (A beta)-induced cytotoxicity and explore its major active components. Injury of PC 12 cells mediated by A beta(25-35) was adopted to assess the cytoprotective effects of DAW aqueous extract and various fractions. Salvianolic acid B, a polyphenol compound isolated from Salvia miltiorrhiza, was employed as a positive control agent due to its markedly protective effect against neurotoxicity of amyloid beta. Five chemical fractions (i.e. alkaloids, essential oil, saponins, iridoid glucoside and polysaccharides) were prepared for activity test and analyzed by HPLC for active components identification. In addition, Akebia saponin D (the most important compound in DAW saponins) and hederagenin (the mother nucleus of akebia saponin D) were prepared for testing of their activity. DAW water extract, saponins fraction and akebia saponin D had the neuroprotective capacity to antagonize A beta(25-35)-induced cytotoxicity in PC 12 cells. In contrast, other fractions and hederagenin had no cytoprotective action. This research suggests that DAW may represent a potential treatment strategy for AD and akebia saponin D is one of its active components.Cell Biology International 08/2009; 33(10):1102-10. DOI:10.1016/j.cellbi.2009.06.028 · 1.64 Impact Factor
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ABSTRACT: Background: Alzheimer's disease (AD) is one of the most pressing and difficult to diagnose unmet diseases confronting industrialized countries. It is characterized by the appearance in the post mortem autopsied AD brain of amyloid plaques containing Aβ42 and paired helical filaments in neurofibrillary tangles with hyperphosphorylated tau. Objective: To investigate the potential of proteomics approaches for AD diagnosis. Methods: This reviews focuses on studies of the altered phosphorylation of tau and other proteins as detected in brain biopsy, cerebral spinal fluid (CSF) and blood samples. Results/conclusion: Detection of decreased Aβ42, and increased total and hyperphosphorylated tau in CSF from AD patients can provide a fairly reliable diagnosis. Furthermore, very recent studies have demonstrated altered levels of cytokines in plasma and differential gene expression and protein phosphorylation in peripheral blood mononuclear cells from AD patients. Identification of the roles of these proteins may provide valuable insights into the underlying molecular pathology of AD and possible sites for therapeutic intervention.Expert Opinion on Medical Diagnostics 05/2008; 2(5):577-91. DOI:10.1517/17530059.2.5.577