c-Jun N-terminal Kinase Regulates Soluble Aβ Oligomers and Cognitive Impairment in AD Mouse Model

Sclip, Alessandra; Antoniou, Xanthi; Colombo, Alessio; Camici, Giovanni G.; Pozzi, Laura; Cardinetti, Daniele; Feligioni, Marco; Veglianese, Pietro; Bahlmann, Ferdinand H.; Cervo, Luigi; Balducci, Claudia; Costa, Cinzia; Tozzi, Alessandro; Calabresi, Paolo; Forloni, Gianluigi; Borsello, Tiziana

doi:10.1074/jbc.m111.297515

Cited by 75 publications

(80 citation statements)

References 45 publications

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“…29 We here explored the effect of D-JNKI1 treatment on long-term depression (LTD). LTD is an activity-dependent physiological phenomenon occurring in the dentate gyrus (DG) that also involves synaptic release of glutamate.…”

Section: Resultsmentioning

confidence: 99%

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c-Jun N-terminal kinase has a key role in Alzheimer disease synaptic dysfunction in vivo

et al. 2014

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Altered synaptic function is considered one of the first features of Alzheimer disease (AD). Currently, no treatment is available to prevent the dysfunction of excitatory synapses in AD. Identification of the key modulators of synaptopathy is of particular significance in the treatment of AD. We here characterized the pathways leading to synaptopathy in TgCRND8 mice and showed that c-Jun N-terminal kinase (JNK) is activated at the spine prior to the onset of cognitive impairment. The specific inhibition of JNK, with its specific inhibiting peptide D-JNKI1, prevented synaptic dysfunction in TgCRND8 mice. D-JNKI1 avoided both the loss of postsynaptic proteins and glutamate receptors from the postsynaptic density and the reduction in size of excitatory synapses, reverting their dysfunction. This set of data reveals that JNK is a key signaling pathway in AD synaptic injury and that its specific inhibition offers an innovative therapeutic strategy to prevent spine degeneration in AD.

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Section: Resultsmentioning

confidence: 99%

“…27, 29 We used a ‘post-symptomatic' treatment as it is clinically more relevant. This treatment protocol was also supported by our results that demonstrate that JNK activation started at 2 months and persisted with a significant increase during AD progression.…”

Section: Discussionmentioning

confidence: 99%

c-Jun N-terminal kinase has a key role in Alzheimer disease synaptic dysfunction in vivo

et al. 2014

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“…[4][5][6][7][8][9][10][11] However, whether specific inhibition of central JNK activation would prevent the development of different pathological features remains to be fully investigated in vivo. [4][5][6][7][8][9][10][11] However, whether specific inhibition of central JNK activation would prevent the development of different pathological features remains to be fully investigated in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 A growing body of evidence has shown that c-Jun N-terminal kinase (JNK), known as a stress-activated protein kinase, is involved in several pathophysiological processes of AD. [4][5][6][7][8][9][10][11] In addition, it has been proven that JNK activation mediates APP phosphorylation at threonine 668 site to facilitate Ab production in cultured cells, suggesting that active JNK is involved in Ab production. [4][5][6][7][8][9][10][11] In addition, it has been proven that JNK activation mediates APP phosphorylation at threonine 668 site to facilitate Ab production in cultured cells, suggesting that active JNK is involved in Ab production.…”

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confidence: 99%

Inhibition of c‐Jun N‐terminal kinase activation reverses Alzheimer disease phenotypes in APPswe/PS1dE9 mice

Zhou

Wang

et al. 2015

Annals of Neurology

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Our findings demonstrate that chronic SP600125 treatment is powerfully effective in slowing down disease progression by markedly reducing multiple pathological features and ameliorating cognitive deficits associated with AD. This study highlights the concept that active JNK actually contributes to the development of the disease, and provides critical preclinical evidence that specific inhibition of JNK activation by SP600125 treatment may be a novel promising disease-modifying therapeutic strategy for the treatment of AD.

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“…58-60,[136][137][138][139][140][141] More recently, Ngoei et al identified the peptides L-PYC71N and D-PYC98 from a yeast twohybrid screen of a biodiverse gene fragment library 142,143. Both peptides are pan-JNK inhibitors…”

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confidence: 96%

Inhibitors of c-Jun N-Terminal Kinases: An Update

2014

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The c-Jun N-terminal kinases (JNKs) are serine/threonine kinases implicated in the pathogenesis of various diseases. Recent advances in the development of novel inhibitors of JNKs will be reviewed. Significant progress in the design of JNK inhibitors displaying selectivity versus other kinases has been achieved within the past 4 years. However, the development of isoform selective JNK inhibitors is still an open task.

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c-Jun N-terminal Kinase Regulates Soluble Aβ Oligomers and Cognitive Impairment in AD Mouse Model

Cited by 75 publications

References 45 publications

c-Jun N-terminal kinase has a key role in Alzheimer disease synaptic dysfunction in vivo

c-Jun N-terminal kinase has a key role in Alzheimer disease synaptic dysfunction in vivo

Inhibition of c‐Jun N‐terminal kinase activation reverses Alzheimer disease phenotypes in APPswe/PS1dE9 mice

Inhibitors of c-Jun N-Terminal Kinases: An Update

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