Inhibition of c-Jun kinase provides neuroprotection in a model of Alzheimer's disease

Braithwaite, Steven P.; Schmid, Ralf S.; Dong, He; Sung, Mei-Li A.; Cho, Seongeon; Resnick, Lauren B.; Monaghan, Michael M.; Hirst, Warren D.; Essrich, Christian; Reinhart, Peter H.; Lo, Donald C.

doi:10.1016/j.nbd.2010.04.015

Cited by 76 publications

(66 citation statements)

References 42 publications

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“…The basal levels of pJNK1-3 were nominally higher in ␣4␤2-nAChR-transfected cells as compared with mock-transfected cells. This up-regulation is consistent with the recent studies demonstrating the neuroprotective effect of inhibiting JNK activity in rodent AD models (26,27).…”

Section: Differential Activation Of Mapk Pathways Following Sustainedsupporting

confidence: 92%

“…Acute-short-term application of A␤, or often a toxic C-terminal fragment of A␤ (A␤ [25][26][27][28][29][30][31][32][33][34][35] ) has been found to activate several signaling pathways (2), including the MAPK cascade (5,6,16,36). Here, we examined the impact of prolonged exposure to A␤ on intracellular signaling in a model cultured nerve cell system (differentiated clonal neuroblastoma cells) selectively expressing ␣4␤2-nAChRs, as defined high-affinity targets for A␤ (22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

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Nicotinic Acetylcholine Receptors Sensitize a MAPK-linked Toxicity Pathway on Prolonged Exposure to β-Amyloid

Arora

Cheng

Nichols

2015

Journal of Biological Chemistry

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Section: Differential Activation Of Mapk Pathways Following Sustainedsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Nicotinic Acetylcholine Receptors Sensitize a MAPK-linked Toxicity Pathway on Prolonged Exposure to β-Amyloid

Arora

Cheng

Nichols

2015

Journal of Biological Chemistry

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“…Consistent with a role of JNK signaling in mediating A␤ toxicity (Morishima et al, 2001), recent studies have demonstrated the neuroprotective effect of inhibiting JNK activity in rodent AD models (Braithwaite et al, 2010;Ramin et al, 2011). Furthermore, JNK-mediated APP phosphorylation at Thr (T) 668 has been proposed as a mechanism to prevent APP degradation and increase A␤ production in a neuroglioma cell line (Colombo et al, 2009).…”

Section: Introductionmentioning

confidence: 74%

The Loss of c-Jun N-Terminal Protein Kinase Activity Prevents the Amyloidogenic Cleavage of Amyloid Precursor Protein and the Formation of Amyloid PlaquesIn Vivo

Mazzitelli¹,

Xu²,

Ferrer³

et al. 2011

J. Neurosci.

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Phosphorylation plays a central role in the dynamic regulation of the processing of the amyloid precursor protein (APP) and the production of amyloid-␤ (A␤), one of the clinically most important factors that determine the onset of Alzheimer's disease (AD). This has led to the hypothesis that aberrant A␤ production associated with AD results from regulatory defects in signal transduction. However, conflicting findings have raised a debate over the identity of the signaling pathway that controls APP metabolism. Here, we demonstrate that activation of the c-Jun N-terminal protein kinase (JNK) is essential for mediating the apoptotic response of neurons to A␤. Furthermore, we discovered that the functional loss of JNK signaling in neurons significantly decreased the number of amyloid plaques present in the brain of mice carrying familial AD-linked mutant genes. This correlated with a reduction in A␤ production. Biochemical analyses indicate that the phosphorylation of APP at threonine 668 by JNK is required for ␥-mediated cleavage of the C-terminal fragment of APP produced by ␤-secretase. Overall, this study provides genetic evidence that JNK signaling is required for the formation of amyloid plaques in vivo. Therefore, inhibition of increased JNK activity associated with aging or with a pathological condition constitutes a potential strategy for the treatment of AD.

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“…24,25,37,38) Therefore, we investigated the effects of P. multiflorum and S. commixta extracts intake on JNK or EGFR activity. As shown in Figs.…”

mentioning

confidence: 99%

<i>In Vivo</i> Screening of Traditional Medicinal Plants for Neuroprotective Activity against Aβ42 Cytotoxicity by Using <i>Drosophila</i> Models of Alzheimer’s Disease

Liu

Lee

Kim

et al. 2015

Biological & Pharmaceutical Bulletin

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Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by progressive neuronal loss with amyloid β-peptide (Aβ) plaques. Despite several drugs currently used to treat AD, their beneficial effects on AD progress remains under debate. Here, we established a rapid in vivo screening system using Drosophila AD models to assess the neuroprotective activities of medicinal plants that have been used in traditional Chinese medicine. Among 23 medicinal plants tested, the extracts from five plants, Coriandrum sativum, Nardostachys jatamansi, Polygonum multiflorum (P. multiflorum), Rehmannia glutinosa, and Sorbus commixta (S. commixta), showed protective effects against the Aβ42 neurotoxicity. We further characterized the neuroprotective activity of ethanol extracts from P. multiflorum and S. commixta. Aβ42-expressing flies that we used showed AD neurological phenotypes, such as decreased survival and motility and increased cell death and reactive oxygen species level. However, feeding these flies extracts from P. multiflorum or S. commixta showed strong suppression of such phenotypes. Similar results were observed in human cells, so that the treatment of P. multiflorum and S. commixta extracts increased the viability of Aβ-treated SH-SY5Y cells. Moreover, 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside, one of the main constituents of P. multiflorum, also showed similar protective activity against Aβ42 cytotoxicity in both Drosophila and human cells. Taken together, our results suggest that both P. multiflorum and S. commixta have therapeutic potential for the treatment of neurodegenerative diseases, such as AD.Key words amyloid β-peptide 42 (Aβ42); Alzheimer's disease; Drosophila; Polygonum multiflorum; reactive oxygen species (ROS); Sorbus commixta Alzheimer's disease (AD) is a common neurodegenerative disease that is characterized by progressive neural loss caused by amyloid β-peptide (Aβ) plaques and cognitive deficits. 1,2) During disease progression, neurotoxic forms of Aβ cause neuronal damages via various cellular abnormalities such as increased oxidative damage, impaired energy metabolism, disrupted cellular calcium homeostasis, and increased inflammatory response.2,3) Several drugs have been approved to treat AD, given the dysfunction of cholinergic and glutamatergic neurotransmission; they function as acetylcholinesterase inhibitors or N-methyl-D-aspartate (NMDA) receptor antagonists. 4,5) However, the beneficial effects of these drugs during the progression of AD are still in question. 6) Due to its complex etiology, a combination therapy including the use of medicinal plants with effective components has been proposed as an alternative choice for treatment of AD. 7,8) Chinese traditional medicine has employed a variety of herbs to treat dementia, and a number of neuroprotective agents were isolated from these herbs. 7,8) For example, Polygonum multiflorum (P. multiflorum; syn. Reynoutria multiflora) has been known as a tonic and antiaging agent in many remedies for centuries, and...

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Inhibition of c-Jun kinase provides neuroprotection in a model of Alzheimer's disease

Cited by 76 publications

References 42 publications

Nicotinic Acetylcholine Receptors Sensitize a MAPK-linked Toxicity Pathway on Prolonged Exposure to β-Amyloid

Nicotinic Acetylcholine Receptors Sensitize a MAPK-linked Toxicity Pathway on Prolonged Exposure to β-Amyloid

The Loss of c-Jun N-Terminal Protein Kinase Activity Prevents the Amyloidogenic Cleavage of Amyloid Precursor Protein and the Formation of Amyloid PlaquesIn Vivo

<i>In Vivo</i> Screening of Traditional Medicinal Plants for Neuroprotective Activity against Aβ42 Cytotoxicity by Using <i>Drosophila</i> Models of Alzheimer’s Disease

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