CDK5 activator protein p25 preferentially binds and activates GSK3β

Chow, Hei Man; Guo, Dong; Zhou, Jiechao; Zhang, Guanyun; Li, Huifang; Herrup, Karl; Zhang, Jie

doi:10.1073/pnas.1402627111

Cited by 69 publications

(50 citation statements)

References 63 publications

(61 reference statements)

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“…Elevated p25 levels are observed in AD patients [35]. CDK5 activator protein p25 preferentially binds and activates GSK3β [36]. All these data supported the hypothesis that Cdk5/p25 acts as a master regulator of neuronal cell death in AD, Parkinson's disease and several neurodegenerative diseases, [34].…”

Section: Discussionmentioning

confidence: 68%

AF710B, a Novel M1/σ1 Agonist with Therapeutic Efficacy in Animal Models of Alzheimer's Disease

Fisher

Bezprozvanny²,

et al. 2015

Neurodegener Dis

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We previously developed orthosteric M1 muscarinic agonists (e.g. AF102B, AF267B and AF292), which act as cognitive enhancers and potential disease modifiers. We now report on a novel compound, AF710B, a highly potent and selective allosteric M1 muscarinic and σ1 receptor agonist. AF710B exhibits an allosteric agonistic profile on the M1 muscarinic receptor; very low concentrations of AF710B significantly potentiated the binding and efficacy of carbachol on M1 receptors and their downstream effects (p-ERK1/2, p-CREB). AF710B (1-30 µg/kg, p.o.) was a potent and safe cognitive enhancer in rats treated with the M1 antagonist trihexyphenidyl (passive avoidance impairment). These effects of AF710B involve σ1 receptor activation. In agreement with its antiamnesic properties, AF710B (at 30 nM), via activation of M1 and a possible involvement of σ1 receptors, rescued mushroom synapse loss in PS1-KI and APP-KI neuronal cultures, while AF267B (1 µM) was less potent in PS1-KI and ineffective in APP-KI models, respectively. In female 3xTg-AD mice, AF710B (10 µg/kg, i.p./daily/2 months) (i) mitigated cognitive impairments in the Morris water maze; (ii) decreased BACE1, GSK3β activity, p25/CDK5, neuroinflammation, soluble and insoluble Aβ₄₀, Aβ₄₂, plaques and tau pathologies. AF710B differs from conventional σ1 and M1 muscarinic (orthosteric, allosteric or bitopic) agonists. These results highlight AF710B as a potential treatment for Alzheimer's disease (e.g. improving cognitive deficits, synaptic loss, amyloid and tau pathologies, and neuroinflammation) with a superior profile over a plethora of other therapeutic strategies.

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Section: Discussionmentioning

confidence: 68%

AF710B, a Novel M1/σ1 Agonist with Therapeutic Efficacy in Animal Models of Alzheimer's Disease

Fisher

Bezprozvanny²,

et al. 2015

Neurodegener Dis

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“…GSK3 also was recently found to bind to inositol hexakisphosphate-1, which enhanced GSK3 activity (Chakraborty et al, 2013). Other interactions include glycogen synthase kinase 3β interaction protein (GSKIP) that appears to function as a member of the A-kinase anchoring proteins (AKAP) family and inhibits GSK3 in the Wnt signaling complex (Chou et al, 2006; Hundsrucker et al, 2010), protein 4.1R that regulates GSK3 at microtubules (Ruiz-Saenz et al, 2013), suppressor of fused (Sufu) that is both phosphorylated by GSK3 and links GSK3 to Gli3 in the hedgehog signaling pathway (Kise et al, 2009; Chen et al, 2011) and GSK3 binds, and is activated by, the CDK5 activator protein p25 (Chow et al, 2014). Additionally, as detailed in other reviews, GSK3 is involved in protein complexes that regulate growth cones (Eickholt et al, 2002; Zhou et al, 2004), cell polarity (Etienne-Manneville and Hall, 2003), and focal adhesions (Cai et al, 2006; Kobayashi et al, 2006).…”

Section: Regulation Of Gsk3-mediated Substrate Phosphorylationmentioning

confidence: 99%

Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases

Beurel

Grieco

Jope

2015

Pharmacology & Therapeutics

1,390

1,178

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Glycogen synthase kinase-3 (GSK3) may be the busiest kinase in most cells, with over 100 known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate each substrate, and why was it evolutionarily favorable for GSK3 to assume such a large responsibility? GSK3 must be particularly adaptable for incorporating new substrates into its repertoire, and we discuss the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms regulating GSK3 (predominantly post-translational modifications, substrate priming, cellular trafficking, protein complexes) have been reviewed previously, so here we focus on newly identified complexities in these mechanisms, how each of these regulatory mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate, and how these mechanisms may have contributed to its adaptability as new substrates evolved. The current understanding of the mechanisms regulating GSK3 is reviewed, as are emerging topics in the actions of GSK3, particularly its interactions with receptors and receptor-coupled signal transduction events, and differential actions and regulation of the two GSK3 isoforms, GSK3α and GSK3β. Another remarkable characteristic of GSK3 is its involvement in many prevalent disorders, including psychiatric and neurological diseases, inflammatory diseases, cancer, and others. We address the feasibility of targeting GSK3 therapeutically, and provide an update of its involvement in the etiology and treatment of several disorders.

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“…Since p25 is resistant to ubiquitin-mediated proteolysis and lacks the myristoylation site, the p25/Cdk5 complex is dissociated from the membrane and gains access to various substrates including tau [16]. It is interest to note that p25 preferentially binds and activates GSK-3β [18]. The p25 is accumulated in the brains of patients with AD with increased tau hyperphosphorylation and neuronal apoptosis [19], thereby suggesting that modulation of calpain activity and thus inhibition of p35 proteolysis to p25 are critical for regulation of aberrant activation of Cdk5 as well as GSK-3β under AD conditions.…”

Section: Introductionmentioning

confidence: 99%

Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation

Annamalai

Won

Choi

et al. 2015

Biochemical and Biophysical Research Communications

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Hyperphosphorylation and polymerization of microtubule-associated protein tau into paired helical filaments (PHFs) is one of the hallmarks of Alzheimer’s disease (AD). Here we report that neuronal tau hyperphosphorylation under AD conditions is regulated by Snitrosoglutathione (GSNO), an endogenous nitric oxide carrier molecule. In cultured rat cortical primary neurons, we observed that GSNO treatment decreased the β-amyloid (Aβ25–35)-induced pathological tau hyperphosphorylation (Ser396, Ser404, and Ser202/Thr205). The decreased tau hyperphosphorylation correlated with decreased activity of calpain and decreased p35 proteolysis into p25 and Cdk5 activation. GSNO treatment also attenuated the Aβ25–35-induced activation of GSK-3β which is known to play critical role in tau hyperphosphorylation in addition to Cdk5. Consistent with above studies using cultured neurons, we also observed that systemic GSNO treatment of transgenic mouse model of AD (APPSw/PS1dE9) attenuated calpain-mediated p35 proteolysis and Cdk5/GSK-3β activities as well as tau hyperphosphorylation. In addition, GSNO treatment provided neuro- and cognitive protection in APPSw/PS1dE9 mice. This study describing the GSNO-mediated regulation of tau hyperphosphorylation and cognitive function, for the first time, suggests for therapeutic potential of GSNO as neuro- and cognitive-protective agent for AD.

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CDK5 activator protein p25 preferentially binds and activates GSK3β

Cited by 69 publications

References 63 publications

AF710B, a Novel M1/σ1 Agonist with Therapeutic Efficacy in Animal Models of Alzheimer's Disease

AF710B, a Novel M1/σ1 Agonist with Therapeutic Efficacy in Animal Models of Alzheimer's Disease

Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases

Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation

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