Liu, F, Grundke-Iqbal, I, Iqbal, K and Gong, CX. Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur J Neurosci 22: 1942-1950

Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York 10314, USA.
European Journal of Neuroscience (Impact Factor: 3.18). 11/2005; 22(8):1942-50. DOI: 10.1111/j.1460-9568.2005.04391.x
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Abnormal hyperphosphorylation of tau is believed to lead to neurofibrillary degeneration in Alzheimer's disease (AD) and other tauopathies. Recent studies have shown that protein phosphatases (PPs) PP1, PP2A, PP2B and PP5 dephosphorylate tau in vitro, but the exact role of each of these phosphatases in the regulation of site-specific phosphorylation of tau in the human brain was unknown. Hence, we investigated the contributions of these PPs to the regulation of tau phosphorylation quantitatively. We found that these four phosphatases all dephosphorylated tau at Ser199, Ser202, Thr205, Thr212, Ser214, Ser235, Ser262, Ser396, Ser404 and Ser409, but with different efficiencies toward different sites. The K(m) values of tau dephosphorylation catalysed by PP1, PP2A and PP5 were 8-12 microm, similar to the intraneuronal tau concentration of human brain, whereas the K(m) of PP2B was fivefold higher. PP2A, PP1, PP5 and PP2B accounted for approximately 71%, approximately 11%, approximately 10% and approximately 7%, respectively, of the total tau phosphatase activity of human brain. The total phosphatase activity and the activities of PP2A and PP5 toward tau were significantly decreased, whereas that of PP2B was increased in AD brain. PP2A activity negatively correlated to the level of tau phosphorylation at the most phosphorylation sites in human brains. Our findings indicate that PP2A is the major tau phosphatase that regulates its phosphorylation at multiple sites in human brain. The abnormal hyperphosphorylation of tau is partially due to a downregulation of PP2A activity in AD brain.

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Available from: Cheng-Xin Gong, Oct 08, 2015
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    • "Several protein kinases, such as glycogen synthase kinase-3b (GSK-3b), extracellular signal-regulated kinases (ERK1/2), cyclin dependent kinases 5 (CDK5), cAMP-dependent protein kinase (PKA), calcium/calmodulin-dependent protein kinase II (CaMK-II), and JNKs, have been implicated in hyperphosphorylation of tau in AD (Gong et al. 2010). Tau phosphorylation is also regulated by protein phosphatase 2A (PP2A) (Gong et al. 2000), which accounts for over 70 % of total tau 104 Cell Mol Neurobiol (2015) 35:101–110 123 Author's personal copy phosphatase activity in the mammalian brain (Liu et al. 2005). Increased tau hyperphosphorylation with concurrent activation of GSK-3b, CDK5, and CaMK-II, as well as inhibition of PP2A is observed in a rat model of CCH, which shows spatial learning/memory deficits (Yao et al. 2012). "
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    ABSTRACT: Chronic cerebral hypoperfusion (CCH) is a common consequence of various cerebral vascular disorders and hemodynamic and blood changes. Recent studies have revealed an important role of CCH in neurodegeneration and dementia, including vascular dementia and Alzheimer's disease (AD). This article reviews the recent advances in understanding CCH-induced neurodegeneration and AD-related brain pathology and cognitive impairment. We discuss the causes and assessment of CCH, the possible mechanisms by which CCH promotes Alzheimer-like pathology and neurodegeneration, and animal models of CCH. It appears that CCH promotes neurodegeneration and AD through multiple mechanisms, including induction of oxidative stress, Aβ accumulation and aggravation, tau hyperphosphorylation, synaptic dysfunction, neuronal loss, white matter lesion, and neuroinflammation. Better understanding of the mechanisms of CCH will help develop therapeutic strategies for preventing and treating neurodegeneration, including sporadic AD and vascular dementia, caused by CCH.
    Cellular and Molecular Neurobiology 10/2014; 35(1). DOI:10.1007/s10571-014-0127-9 · 2.51 Impact Factor
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    • "Initially, PP1 activates GSK3β through dephosphorylation of Ser9 (Bennecib et al., 2000; Hernandez et al., 2010), and PP2A dephosphorylates and regulates AKT, inhibiting its activity on GSK3β (Mora et al., 2002; Resjo et al., 2002). Thus, phosphatases influence Tau phosphorylation through several mechanisms, and in a pathological condition such as AD where phosphatase activity is decreased (Liu et al., 2005), these enzymes are key factors in the development of the disease (Figure 1). "
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    ABSTRACT: Alzheimer's disease (AD) is the most common cause of dementia worldwide. One of the main pathological changes that occurs in AD is the intracellular accumulation of hyperphosphorylated Tau protein in neurons. Cyclin-dependent kinase 5 (CDK5) is one of the major kinases involved in Tau phosphorylation, directly phosphorylating various residues and simultaneously regulating various substrates such as kinases and phosphatases that influence Tau phosphorylation in a synergistic and antagonistic way. It remains unknown how the interaction between CDK5 and its substrates promotes Tau phosphorylation, and systemic approaches are needed that allow an analysis of all the proteins involved. In this review, the role of the CDK5 signaling pathway in Tau hyperphosphorylation is described, an in silico model of the CDK5 signaling pathway is presented. The relationship among these theoretical and computational models shows that the regulation of Tau phosphorylation by PP2A and glycogen synthase kinase 3β (GSK3β) is essential under basal conditions and also describes the leading role of CDK5 under excitotoxic conditions, where silencing of CDK5 can generate changes in these enzymes to reverse a pathological condition that simulates AD.
    Frontiers in Aging Neuroscience 09/2014; 6:232. DOI:10.3389/fnagi.2014.00232 · 4.00 Impact Factor
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    • "In AD, total phosphatase activity is reduced by approximately 50% (Liu et al, 2005). PPP2CA is the most efficient phosphatase acting on hyperphosphorylated tau (Liu et al, 2005). Although previous studies reported direct regulation of PPP2CA by miR-125b (Le et al, 2011), PPP2CA protein levels are not downregulated upon miR-125b overexpression in primary rat neurons under our conditions (Fig 3A). "
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    ABSTRACT: Sporadic Alzheimer's disease (AD) is the most prevalent form of dementia, but no clear disease-initiating mechanism is known. Aβ deposits and neuronal tangles composed of hyperphosphorylated tau are characteristic for AD. Here, we analyze the contribution of microRNA-125b (miR-125b), which is elevated in AD. In primary neurons, overexpression of miR-125b causes tau hyperphosphorylation and an upregulation of p35, cdk5, and p44/42-MAPK signaling. In parallel, the phosphatases DUSP6 and PPP1CA and the anti-apoptotic factor Bcl-W are downregulated as direct targets of miR-125b. Knockdown of these phosphatases induces tau hyperphosphorylation, and overexpression of PPP1CA and Bcl-W prevents miR-125b-induced tau phosphorylation, suggesting that they mediate the effects of miR-125b on tau. Conversely, suppression of miR-125b in neurons by tough decoys reduces tau phosphorylation and kinase expression/activity. Injecting miR-125b into the hippocampus of mice impairs associative learning and is accompanied by downregulation of Bcl-W, DUSP6, and PPP1CA, resulting in increased tau phosphorylation in vivo. Importantly, DUSP6 and PPP1CA are also reduced in AD brains. These data implicate miR-125b in the pathogenesis of AD by promoting pathological tau phosphorylation.
    The EMBO Journal 07/2014; 33(15). DOI:10.15252/embj.201387576 · 10.43 Impact Factor
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