The interrelationship between selective tau phosphorylation and microtubule association

Xie, Han Qing; Litersky, Joel M.; Hartigan, Judith A.; Jope, Richard S.; Johnson, Gail V.W.

doi:10.1016/s0006-8993(98)00407-7

Cited by 61 publications

(48 citation statements)

References 85 publications

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“…The results presented here are in vivo evidence showing that an nAChR agonist, such as nicotine, increases tau phosphorylation at Ser-202 and Thr-181. These two residues are known to modulate the kinetics of tau binding to microtubules, which can eventually lead to microtubule instability (29). These data also support the hypothesis that nAChRs may be a link between A␤ and tau pathology, although other mechanisms underlying A␤-induced tau pathology certainly cannot be excluded, because it is likely that multiple pathways are responsible for A␤-induced neurotoxicity.…”

Section: Figsupporting

confidence: 65%

“…The increase in tau phosphorylation was also evident by quantitative Western blot analysis by using the phospho-specific anti-tau antibody, AT8, which recognizes phosphorylated tau at Ser-202. The phosphorylation of tau at Ser-202 and Thr-181, induced by chronic nicotine exposure, modulates the kinetics of tau binding to microtubules leading to the destabilization of the neuronal cytoskeleton (29).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease

Oddo

Caccamo

Green

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

191

130

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The association between nicotinic acetylcholine receptor (nAChR) dysfunction and cognitive decline in Alzheimer's disease (AD) has been widely exploited for its therapeutic potential. The effects of chronic nicotine exposure on A␤ accumulation have been studied in both humans and animal models, but its therapeutic efficacy for AD neuropathology is still unresolved. To date, no in vivo studies have addressed the consequences of activating nAChRs on tau pathology. To determine the effects of chronic nicotine administration on A␤ and tau pathology, we chronically administrated nicotine to a transgenic model of AD (3xTg-AD) in their drinking water. Here, we show that chronic nicotine intake causes an up-regulation of nicotinic receptors, which correlated with a marked increase in the aggregation and phosphorylation state of tau. These data show that nicotine exacerbates tau pathology in vivo. The increase in tau phosphorylation appears to be due to the activation of p38-mitogen-activated protein kinase, which is known to phosphorylate tau in vivo and in vitro. We also show that the 3xTg-AD mice have an age-dependent reduction of ␣7nAChRs compared with age-matched nontransgenic mice in specific brain regions. The reduction of ␣7nAChRs is first apparent at 6 months of age and is restricted to brain regions that show intraneuronal A␤42 accumulation. Finally, this study highlights the importance of testing compounds designed to ameliorate AD pathology in a model with both neuropathological lesions because of the differential effects it can have on either A␤ or tau.T he loss of cholinergic neurons is a critical event in the pathogenesis of Alzheimer's disease (AD) (1, 2). Acetylcholine (ACh) is a key neuromodulator in the synaptic mechanisms involved with learning and memory (3) and acts through two major receptor subtypes: nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs). Whereas mAChRs are metabotropic, nAChRs are ligand-gated ion channels formed by a combination of five subunits (␣, ␤, ␥, ␦, and ), each encoded by a member of a gene superfamily (4). The ␣7 and ␣4␤2 are two of the major nicotinic receptors subtypes present in the brain (4, 5). For the past several years, a mainstay of AD therapy has been aimed at inhibiting acetylcholinesterase, the enzyme responsible for degrading ACh in the synaptic cleft, and thereby increasing ACh levels in the brain (6). These compounds slow the phenotypical memory impairments; however, their effectiveness is diminished over time.The AD brain is characterized by two pathological hallmarks: amyloid plaques, which are mainly composed of the A␤ peptide, and neurofibrillary tangles (NFTs), which consist of hyperphosphorylated tau protein. Several studies have shown that nAChRs are selectively reduced in the AD brain, particularly in regions harboring plaques and neurofibrillary tangles, suggesting a potential relationship between nicotinic receptors and AD neuropathology (5, 7-9). Notably, chronic nicotine treatment has also been shown to redu...

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Section: Figsupporting

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease

Oddo

Caccamo

Green

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

191

130

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“…Such an interaction may induce conformational changes in PP2A, which partially or completely conceal the catalytic site, preventing efficient access to substrates. The inhibition of PP2A activity by MTs also provides an explanation for reports that MT depolymerization induces okadaic acid-sensitive dephosphorylation of tau in cultured cells (11,44). Together, these results underscore the possible importance of MT dynamics in the regulation of the phosphorylation state of PP2A-sensitive substrates, including tau.…”

Section: Discussionsupporting

confidence: 53%

Molecular Interactions among Protein Phosphatase 2A, Tau, and Microtubules

Sontag¹,

Nunbhakdi-Craig²,

Lee³

et al. 1999

Journal of Biological Chemistry

278

116

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Hyperphosphorylated forms of the neuronal microtubule (MT)-associated protein tau are major components of Alzheimer's disease paired helical filaments. Previously, we reported that AB␣C, the dominant brain isoform of protein phosphatase 2A (PP2A), is localized on MTs, binds directly to tau, and is a major tau phosphatase in cells. We now describe direct interactions among tau, PP2A, and MTs at the submolecular level. Using tau deletion mutants, we found that AB␣C binds a domain on tau that is indistinguishable from its MT-binding domain. AB␣C binds directly to MTs through a site that encompasses its catalytic subunit and is distinct from its binding site for tau, and AB␣C and tau bind to different domains on MTs. Specific PP2A isoforms bind to MTs with distinct affinities in vitro, and these interactions differentially inhibit the ability of PP2A to dephosphorylate various substrates, including tau and tubulin. Finally, tubulin assembly decreases PP2A activity in vitro, suggesting that PP2A activity can be modulated by MT dynamics in vivo. Taken together, these findings indicate how structural interactions among AB␣C, tau, and MTs might control the phosphorylation state of tau. Disruption of these normal interactions could contribute significantly to development of tauopathies such as Alzheimer's disease. The axonal microtubule (MT)1 -associated protein (MAP) tau (1, 2) is encoded by one alternatively spliced gene that directs the synthesis of six tau isoforms in human brain (3). The C-terminal half of brain tau encompasses three or four contiguous MT-binding repeats that act synergistically with regions flanking both sides of the repeats to support higher affinity MT binding (4 -6). All tau isoforms in human brain contain 21 serine/threonine phosphorylation sites (7), some of which modulate MT binding of tau (8 -11). Only a few sites on tau are phosphorylated at any moment in normal adults (12,13). In Alzheimer's disease brain, however, tau is more heavily phosphorylated (12, 13), due in part to decreased tau phosphatase activity (13,14). Hyperphosphorylated tau is the principal component of Alzheimer's disease paired helical filaments and neurofibrillar lesions present in several other neurodegenerative disorders (15) and has very low affinity for MTs (16,17). Although non-phosphorylated tau can assemble into paired helical filament-like filaments in vitro (18 -21), it is reasonable to hypothesize that changes in tau phosphorylation are decisive events in paired helical filament biogenesis in vivo.To study how tau phosphorylation is regulated, we have been focusing on protein phosphatase 2A (PP2A), a heterotrimeric enzyme that comprises one catalytic C subunit, one non-catalytic A subunit, and one of several structurally distinct, regulatory B subunits (22). We previously reported that PP2A is likely to be a major tau phosphatase in vivo (23). Initially, we found that a pool of AB␣C, the major PP2A isoform in brain (22), is associated with MTs in brain and cultured cells (17). Subsequently, we determined that ...

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“…Briefly, DLD-1 and SW480 cells were preincubated with 100 nM Okadaic Acid (concentration commonly used in cell-based assays (Mistry et al, 1998;Xie et al, 1998), which efficiently inhibits PP2A without affecting protein phosphatase 1 (PP1) (Favre et al, 1997;Nunbhakdi-Craig et al, 2002;Smal et al, 2004)), or with vehicle control. Cells were subsequently incubated with aspirin (5 mM) in the presence of Okadaic acid or vehicle control during a time course (as indicated).…”

Section: Resultsmentioning

confidence: 99%

Effect of aspirin on the Wnt/β-catenin pathway is mediated via protein phosphatase 2A

et al. 2006

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Nonsteroidal anti-inflammatory drugs show chemopreventive efficacy in colon cancer, but the mechanism behind this remains unclear. Elucidating this mechanism is seen as vital to the development of new chemopreventive agents. We studied the effects of aspirin on the oncogenic Wnt/b-catenin pathway activity in colorectal cancer cell lines and observed that aspirin dose-dependently decreased the activity of this pathway, as judged by TCF-driven luciferase activity, reduced Wnt target gene expression and increased phosphorylation of b-catenin by immunoblotting. Furthermore, the ubiquitination and cytoplasmic levels of b-catenin were assessed by immunoblotting, and also the localization of b-catenin was shown by green fluorescent protein-tagged b-catenin and time-lapse fluorescent imaging. Importantly, aspirin treatment caused increased phosphorylation of protein phosphatase 2A (PP2A), an event associated with inhibition of PP2A enzymatic activity, which was confirmed by a reduction in enzymatic PP2A activity. Moreover, this inhibition of PP2A enzymatic activity was essential for the effects of aspirin on the Wnt/b-catenin pathway as shown by transient transfection with PP2A constructs. The findings in this article provide a molecular explanation for the efficacy of aspirin in chemoprevention of colorectal cancer and shows biochemical evidence that PP2A is an important regulator of Wnt/b-catenin pathway activity in these cells.

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The interrelationship between selective tau phosphorylation and microtubule association

Cited by 61 publications

References 85 publications

Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease

Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease

Molecular Interactions among Protein Phosphatase 2A, Tau, and Microtubules

Effect of aspirin on the Wnt/β-catenin pathway is mediated via protein phosphatase 2A

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