The regulation of tau phosphorylation by PCTAIRE 3: Implications for the pathogenesis of Alzheimer's disease

Department of Pathology, Albert Einstein College of Medicine, Forchheimer 526, Bronx, NY 10461, USA.
Neurobiology of Disease (Impact Factor: 5.08). 09/2006; 23(2):398-408. DOI: 10.1016/j.nbd.2006.04.004
Source: PubMed


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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    • "The following commercial anti-tau monoclonal antibodies were used: AT8 (pSer202/pThr202 Fisher cat# MN1020), AT100 (pSer212/pSer214 Fisher cat# MN1060), AT180 (pThr231 Fisher cat# MN1040), AT270 (pThr181 Fisher cat# MN1050), Tau-1 (de-phosphorylated Ser195/Ser198/Ser199/Ser202 Millipore cat# MAB3420), Tau12 (human Tau9-18 Abcam cat# 74137), and Tau46 (Tau404-441 Abcam cat# 22261). The non-commercial monoclonal antibodies were a generous gift of Dr. Peter Davies (Feinstein Institute for Medical Research, Manhasset, NY, USA): CP13 (pSer202), CP27 (human Tau130-150), DA9 (Tau102-140), MC1 (Tau5-15/312-322 conformational antibody), MC6 (pSer235), PHF-1 (pSer396/pSer404), TG3 (pThr231) and TG5 (Tau 220-242) [14], [15], [16], [17], [18], [19], [20], [21]. Purified rabbit polyclonal phospho-tau antibodies were purchased from Invitrogen: anti-pSer199 (44734G), pSer262 (44750G), pSer396 (44752G), pSer404 (44758G), pSer409 (44760G), pSer422 (44774G) and pThr205 (44738G). "
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    ABSTRACT: Aggregates of hyperphosphorylated tau protein are found in a group of diseases called tauopathies, which includes Alzheimer's disease. The causes and consequences of tau hyperphosphorylation are routinely investigated in laboratory animals. Mice are the models of choice as they are easily amenable to transgenic technology; consequently, their tau phosphorylation levels are frequently monitored by Western blotting using a panel of monoclonal/polyclonal anti-tau antibodies. Given that mouse secondary antibodies can recognize endogenous mouse immunoglobulins (Igs) and the possible lack of specificity with some polyclonal antibodies, non-specific signals are commonly observed. Here, we characterized the profiles of commonly used anti-tau antibodies in four different mouse models: non-transgenic mice, tau knock-out (TKO) mice, 3xTg-AD mice, and hypothermic mice, the latter a positive control for tau hyperphosphorylation. We identified 3 tau monoclonal antibody categories: type 1, characterized by high non-specificity (AT8, AT180, MC1, MC6, TG-3), type 2, demonstrating low non-specificity (AT270, CP13, CP27, Tau12, TG5), and type 3, with no non-specific signal (DA9, PHF-1, Tau1, Tau46). For polyclonal anti-tau antibodies, some displayed non-specificity (pS262, pS409) while others did not (pS199, pT205, pS396, pS404, pS422, A0024). With monoclonal antibodies, most of the interfering signal was due to endogenous Igs and could be eliminated by different techniques: i) using secondary antibodies designed to bind only non-denatured Igs, ii) preparation of a heat-stable fraction, iii) clearing Igs from the homogenates, and iv) using secondary antibodies that only bind the light chain of Igs. All of these techniques removed the non-specific signal; however, the first and the last methods were easier and more reliable. Overall, our study demonstrates a high risk of artefactual signal when performing Western blotting with routinely used anti-tau antibodies, and proposes several solutions to avoid non-specific results. We strongly recommend the use of negative (i.e., TKO) and positive (i.e., hypothermic) controls in all experiments.
    Full-text · Article · May 2014 · PLoS ONE
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    • "Proper localization of presynaptic components involves multiple steps, including MT-based transport over long distances and local assembly at presynaptic specializations. As CDK-5 phosphorylates multiple MT-associated proteins and Pctaire3 indirectly phosphorylates tau (Herskovits and Davies, 2006), the CDKs may regulate the localization of presynaptic components by reorganizing the cytoskeleton. We did not detect major alterations to MT polarity and general axon morphology when both CDK pathways are disrupted, suggesting that cytoskeletal rearrangement is unlikely to be the major or only cause of mislocalized presynaptic components. "
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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.
    Full-text · Article · May 2010 · Cell
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    • "Alzheimer's disease is characterized by the presence of two hallmark lesions. One is the formation of neurofibrillary tangles, consisting mainly of aggregated forms of the microtubule-associated protein, tau (Herskovits and Davies, 2006). A second lesion is the presence of senile or neuritic plaques composed of degenerating and dystrophic dendrites or axons in association with extracellular b-amyloid, a fibrillar aggregate of b-amyloid peptide (Andreasen and Blennow, 2002). "
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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.
    Preview · Article · Aug 2009 · Cell Biology International
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