Neuropathogenic role of adenylate kinase-1 in Aβ-mediated tau phosphorylation via AMPK and GSK3β

Park, Hyejin; Kam, Tae In; Kim, Young-Doo; Choi, Hyunwoo; Gwon, Youngdae; Kim, Chang-Soo; Koh, Jun Seok; Jung, Yong‐Keun

doi:10.1093/hmg/dds100

Cited by 73 publications

(56 citation statements)

References 47 publications

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“…The kinase activity of GSK3ß is inhibited upon its phosphorylation by the cyclin-dependent protein kinase CDK5, which can also phosphorylate tau, thus either preventing or promoting tau aggregation, respectively [32]. The trimeric AMP-activated kinase complex AMPK phosphorylates and thus inhibits GSK3ß, but can also itself phosphorylate tau and promote its aggregation [33,34]. The catalytic subunit of AMPK itself is activated by phosphorylation, which can be catalyzed either by the calmodulin-dependent protein kinase kinase CAMKK or a redundant pair of mitogen activated protein kinases (MAPKs), designated as extracellular signal recognition kinases ERK1 or ERK2 [35,36].…”

Section: Posttranslational Modifications Influencing Tau Toxicitymentioning

confidence: 99%

Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

Heinisch¹,

Brandt²

2016

MIC

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In the past decade, yeast have been frequently employed to study the molecular mechanisms of human neurodegenerative diseases, generally by means of heterologous expression of genes encoding the relevant hallmark proteins. However, it has become evident that substantial posttranslational modifications of many of these proteins are required for the development and progression of potentially disease relevant changes. This is exemplified by the neuronal tau proteins, which are critically involved in a class of neurodegenerative diseases collectively called tauopathies and which includes Alzheimer's disease (AD) as its most common representative. In the course of the disease, tau changes its phosphorylation state and becomes hyperphosphorylated, gets truncated by proteolytic cleavage, is subject to O-glycosylation, sumoylation, ubiquitinylation, acetylation and some other modifications. This poses the important question, which of these posttranslational modifications are naturally occurring in the yeast model or can be reconstituted by heterologous gene expression. Here, we present an overview on common modifications as they occur in tau during AD, summarize their potential relevance with respect to disease mechanisms and refer to the native yeast enzyme orthologs capable to perform these modifications. We will also discuss potential approaches to humanize yeast in order to create modification patterns resembling the situation in mammalian cells, which could enhance the value of Saccharomyces cerevisiae and Kluyveromyces lactis as disease models.

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Section: Posttranslational Modifications Influencing Tau Toxicitymentioning

confidence: 99%

Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

Heinisch¹,

Brandt²

2016

MIC

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“…Immunohistochemical studies of AD brain sections using anti-hFcγRIIb (EP888Y; Novus), anti-NeuN (Chemicon), polyclonal anti-Aβ (Zymed), and 4G8 (Signet Laboratories) antibodies were described previously (55). For Western blotting, anti-mFcγRIIb (2.4G2), anti-GFP, anti-p-c-jun, anti-GRP78, anti-CHOP, anti-caspase-12, anti-synaptophysin (Santa Cruz Biotechnology), anti-pJNK, anti-JNK, anti-pERK, anti-ERK (Cell Signaling Technology), anti-α-tubulin, and anti-β-actin (Sigma-Aldrich) antibodies were purchased.…”

Section: Immunohistochemistry and Western Blot Analysismentioning

confidence: 99%

FcγRIIb mediates amyloid-β neurotoxicity and memory impairment in Alzheimer’s disease

et al. 2013

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Amyloid-β (Aβ) induces neuronal loss and cognitive deficits and is believed to be a prominent cause of Alzheimer's disease (AD); however, the cellular pathology of the disease is not fully understood. Here, we report that IgG Fcγ receptor II-b (FcγRIIb) mediates Aβ neurotoxicity and neurodegeneration. We found that FcγRIIb is significantly upregulated in the hippocampus of AD brains and neuronal cells exposed to synthetic Aβ. Neuronal FcγRIIb activated ER stress and caspase-12, and Fcgr2b KO primary neurons were resistant to synthetic Aβ-induced cell death in vitro. Fcgr2b deficiency ameliorated Aβ-induced inhibition of long-term potentiation and inhibited the reduction of synaptic density by naturally secreted Aβ. Moreover, genetic depletion of Fcgr2b rescued memory impairments in an AD mouse model. To determine the mechanism of action of FcγRIIb in Aβ neurotoxicity, we demonstrated that soluble Aβ oligomers interact with FcγRIIb in vitro and in AD brains, and that inhibition of their interaction blocks synthetic Aβ neurotoxicity. We conclude that FcγRIIb has an aberrant, but essential, role in Aβ-mediated neuronal dysfunction.

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“…Several researches have shown alterations in brain energy metabolism are associated with neurodegenerative disorders (Beal 1995(Beal , 2000, (Bubber et al 2005), (Zahid et al 2014). Abnormal hyperphosphorylation of tau have been associated with the activation of several kinases (Park et al 2012). In fact, aβ-peptide aggregates, it generates reactive oxygen species that can induce membrane lipid peroxidation in neurons (Mattson et al 2002).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

“…This is the major regulator of energetic, metabolic monitoring and cellular process in a living cell (Park et al 2012). However, the role of AK expressed in the brain, especially in neurodegenerative disease, is not understood yet (Park et al 2012). Moreover, the expression levels of AK markedly elevated in hippocampal neurons of AD patients and Tg2576 and APP-J20 AD mouse model and it has found AK expression increased in the cortical neurons after exposure to aβ (Park et al 2012).…”

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confidence: 99%

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Amyloid-β peptide absence in short term effects on kinase activity of energy metabolism in mice hippocampus and cerebral cortex

Ianiski

Rech

Nishihira

et al. 2016

An. Acad. Bras. Ciênc.

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Considering that Alzheimer's disease is a prevalent neurodegenerative disease worldwide, we investigated the activities of three key kinases: creatine kinase, pyruvate kinase and adenylate kinase in the hippocampus and cerebral cortex in Alzheimer's disease model. Male adult Swiss mice received amyloid-β or saline. One day after, mice were treated with blank nanocapsules (17 ml/kg) or meloxicam-loaded nanocapsules (5 mg/kg) or free meloxicam (5 mg/kg). Treatments were performed on alternating days, until the end of the experimental protocol. In the fourteenth day, kinases activities were performed. Amyloid-β did not change the kinases activity in the hippocampus and cerebral cortex of mice. However, free meloxicam decrease the creatine kinase activity in mitochondrial-rich fraction in the group induced by amyloid-β, but for the cytosolic fraction, it has raised in the activity of pyruvate kinase activity in cerebral cortex. Further, meloxicam-loaded nanocapsules administration reduced adenylate kinase activity in the hippocampus of mice injected by amyloid-β. In conclusion we observed absence in short-term effects in kinases activities of energy metabolism in mice hippocampus and cerebral cortex using amyloid-β peptide model. These findings established the foundation to further study the kinases in phosphoryltransfer network changes observed in the brains of patients post-mortem with Alzheimer's disease.

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Neuropathogenic role of adenylate kinase-1 in Aβ-mediated tau phosphorylation via AMPK and GSK3β

Cited by 73 publications

References 47 publications

Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

FcγRIIb mediates amyloid-β neurotoxicity and memory impairment in Alzheimer’s disease

Amyloid-β peptide absence in short term effects on kinase activity of energy metabolism in mice hippocampus and cerebral cortex

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