β2 Adrenergic Receptor, Protein Kinase A (PKA) and c-Jun N-terminal Kinase (JNK) Signaling Pathways Mediate Tau Pathology in Alzheimer Disease Models

Wang, Dayong; Fu, Qin; Zhou, Yuan; Xu, Bing; Shi, Qian; Igwe, Benedict; Matt, Lucas; Hell, Johannes; Wisely, Elena V.; Oddo, Salvatore; Xiang, Yang

doi:10.1074/jbc.m112.415141

Cited by 87 publications

(70 citation statements)

References 37 publications

(50 reference statements)

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“…Among the kinases, MAPKs may be the key participators in the neurodegeneration seen in AD [22,23]. ERK and JNK, which are members of the MAPK superfamily, are closely associated with amyloid deposition and tau phosphorylation in AD and diabetes [24][25][26].…”

Section: Discussionmentioning

confidence: 99%

The Neuroprotection of Liraglutide on Alzheimer-Like Learning and Memory Impairment by Modulating the Hyperphosphorylation of Tau and Neurofilament Proteins and Insulin Signaling Pathways in Mice

Xiong

Zheng

Wang

et al. 2013

JAD

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The aim of this study was to investigate the effect of liraglutide on Alzheimer-like learning and memory impairment in mice, which were intracerebroventricularly (i.c.v.) injected with streptozotocin (STZ). Twenty-four mice were randomly divided into three groups: control (CON), AD model (STZ), and liraglutide-treated (LIR). The results show that both hyperphosphorylated tau and neurofilament proteins had deceased protein glycosylation and the tau bound to microtubules was lower in the STZ group compared to the CON group. The expression of JNK phosphorylation was higher and the number of Fluoro-Jade-B-positive degenerative neurons was increased in the STZ group as compared to both the CON and liraglutide groups. Escape latency in the STZ group was longer than that in both the CON and LIR groups, while the number of hidden platform crossings in path length was less than that in the other two groups. Liraglutide decreased the hyperphosphorylation levels of tau and neurofilament proteins, increased protein O-glycosylation, increased tau bound to microtubules, and also significantly improved the learning and memory ability of the mice. These results suggest that the effects of liraglutide on decreasing the hyperphosphorylation of tau and neurofilament proteins by enhancing O-glycosylation of neuronal cytoskeleton protein, improving the JNK and ERK signaling pathway, and reducing neural degeneration may be related to its protective effects on AD-like learning and memory impairment induced by i.c.v. injection of STZ. Our results indicate that GLP-1 analogs represent a novel treatment strategy for Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

The Neuroprotection of Liraglutide on Alzheimer-Like Learning and Memory Impairment by Modulating the Hyperphosphorylation of Tau and Neurofilament Proteins and Insulin Signaling Pathways in Mice

Xiong

Zheng

Wang

et al. 2013

JAD

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“…MAPK8/JNK1-MAPK9/JNK2 activation modulates the phosphorylation of APP, leading to regulation of Aβ levels, 43 as well as to MAPT/ tau phosphorylation in vitro. 44 Furthermore, the M APK8/JNK1-M APK9/ JNK2 pathway is activated in preclinical models of AD, including Tg2576 and Tg2576/PS1P264 L transgenic mice, 45,46 as well as in brains of AD patients. 47 Indeed, we have previously detected a significant activation of MAPK8/JNK1-MAPK9/JNK2-AP1 in oxidative stress in vitro as well as in vivo models, as a pathway that mediates the upregulation of BACE1.…”

Section: Discussionmentioning

confidence: 99%

Aβ1-42 monomers or oligomers have different effects on autophagy and apoptosis

et al. 2014

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“…Mild oxidative stress also induces changes in the subcellular localization of β-secretase that favor the amyloidogenic processing of APP (Tan et al 2013). The β 2 -adrenergic receptor is also implicated in tau pathology and amyloid plaque formation as a result of its modulation of the protein kinase A-JNK signaling axis and stimulation of γ-secretase activity (Ni et al 2006;Wang et al 2013).…”

Section: Mapk Signaling In Neurodegenerative Diseasesmentioning

confidence: 99%

Compromised MAPK signaling in human diseases: an update

2015

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The mitogen-activated protein kinases (MAPKs) in mammals include c-Jun NH2-terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK). These enzymes are serine-threonine protein kinases that regulate various cellular activities including proliferation, differentiation, apoptosis or survival, inflammation, and innate immunity. The compromised MAPK signaling pathways contribute to the pathology of diverse human diseases including cancer and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The JNK and p38 MAPK signaling pathways are activated by various types of cellular stress such as oxidative, genotoxic, and osmotic stress as well as by proinflammatory cytokines such as tumor necrosis factor-α and interleukin 1β. The Ras-Raf-MEK-ERK signaling pathway plays a key role in cancer development through the stimulation of cell proliferation and metastasis. The p38 MAPK pathway contributes to neuroinflammation mediated by glial cells including microglia and astrocytes, and it has also been associated with anticancer drug resistance in colon and liver cancer. We here summarize recent research on the roles of MAPK signaling pathways in human diseases, with a focus on cancer and neurodegenerative conditions.

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β2 Adrenergic Receptor, Protein Kinase A (PKA) and c-Jun N-terminal Kinase (JNK) Signaling Pathways Mediate Tau Pathology in Alzheimer Disease Models

Cited by 87 publications

References 37 publications

The Neuroprotection of Liraglutide on Alzheimer-Like Learning and Memory Impairment by Modulating the Hyperphosphorylation of Tau and Neurofilament Proteins and Insulin Signaling Pathways in Mice

The Neuroprotection of Liraglutide on Alzheimer-Like Learning and Memory Impairment by Modulating the Hyperphosphorylation of Tau and Neurofilament Proteins and Insulin Signaling Pathways in Mice

Aβ1-42 monomers or oligomers have different effects on autophagy and apoptosis

Compromised MAPK signaling in human diseases: an update

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