JNK activation is associated with intracellular β-amyloid accumulation

Shoji, Mikio; Iwakami, Noboru; Takeuchi, Shintaro; Waragai, Masaaki; Suzuki, Misao; Kanazawa, Ichiro; Lippa, Carol F.; Ono, Satoshi; Okazawa, Hitoshi

doi:10.1016/s0169-328x(00)00245-x

Cited by 162 publications

(120 citation statements)

References 49 publications

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“…The levels of JNK3 and p‐JNK are also increased in cerebrospinal fluid (CSF) and are correlated with the rate of cognitive decline in patients with AD (Gourmaud et al ., 2015). In primary hippocampal neurons, the levels of active JNK and phosphorylated IRS1 (Ser616) and tau (Ser422) are significantly increased by exposure to Aβ oligomers (Shoji et al ., 2000). Conversely, JNK inhibition is capable of reducing Aβ toxicity and ameliorating the major pathological features of AD (Troy et al ., 2001; Zhou et al ., 2015).…”

Section: Discussionmentioning

confidence: 99%

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

et al. 2016

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SummaryBrain insulin signaling deficits contribute to multiple pathological features of Alzheimer's disease (AD). Although intranasal insulin has shown efficacy in patients with AD, the underlying mechanisms remain largely unillustrated. Here, we demonstrate that intranasal insulin improves cognitive deficits, ameliorates defective brain insulin signaling, and strongly reduces β‐amyloid (Aβ) production and plaque formation after 6 weeks of treatment in 4.5‐month‐old APPswe/PS1dE9 (APP/PS1) mice. Furthermore, c‐Jun N‐terminal kinase activation, which plays a pivotal role in insulin resistance and AD pathologies, is significantly inhibited. The alleviation of amyloid pathology by intranasal insulin results mainly from enhanced nonamyloidogenic processing and compromised amyloidogenic processing of amyloid precursor protein (APP), and from a reduction in apolipoprotein E protein which is involved in Aβ metabolism. In addition, intranasal insulin effectively promotes hippocampal neurogenesis in APP/PS1 mice. This study, exploring the mechanisms underlying the beneficial effects of intranasal insulin on Aβ pathologies in vivo for the first time, highlights important preclinical evidence that intranasal insulin is potentially an effective therapeutic method for the prevention and treatment of AD.

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Section: Discussionmentioning

confidence: 99%

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

et al. 2016

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“…Different mechanisms have been proposed to explain neurodegeneration, for instance the p53, JNK, and PI3K/Akt signaling pathways are reported to be affected by intracellular A␤ (LaFerla et al, 1996;Shoji et al, 2000;Zhang et al, 2002;Suhara et al, 2003). However, increasing evidence points to a role for molecular chaperones in these neurodegenerative processes (Bonini, 2002;Sakahira et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Heat Shock Protein 70 Participates in the Neuroprotective Response to Intracellularly Expressed β-Amyloid in Neurons

Magrané

Smith²,

Walsh³

et al. 2004

J. Neurosci.

225

186

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Intracellular ␤-amyloid 42 (A␤42) accumulation is increasingly recognized as an early event in the pathogenesis of Alzheimer's disease (AD). We have developed a doxycycline-inducible adenoviral-based system that directs intracellular A␤42 expression and accumulation into the endoplasmic reticulum of primary neuronal cultures in a regulated manner. A␤42 exhibited a perinuclear distribution in cell bodies and an association with vesicular compartments. Virally expressed intracellular A␤42 was toxic to neuronal cultures 24 hr after induction in a dose-dependent manner. A␤42 expression prompted the rapid induction of stress-inducible Hsp70 protein in neurons, and virally mediated Hsp70 overexpression rescued neurons from the toxic effects of intracellular A␤ accumulation. Together, these results implicate the cellular stress response as a possible modulator of A␤-induced toxicity in neuronal cultures.

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“…42,43 In vitro exposure of neurons to Ab peptides has been shown to induce cell death via activation of the JNK signalling cascade. 44,45 Enhanced JNK activation has also been demonstrated in degenerating neurons of postmortem brain sections from AD patients. 45,46 It was recently demonstrated that the C-terminal domain of APP is physically bound to the adapter protein JIP-1b, [10][11][12] which serves as a scaffolding protein for JNKs and upstream kinases such as MKK4, MKK7 and MLKs.…”

Section: App Inhibits Uv-induced Jnk Activation and Cell Deathmentioning

confidence: 97%

“…49 Furthermore, JNK activation increases non-amyloidogenic a-secretase cleavage of APP, 50 indicating the possible existence of a negative feedback loop between APP and the JNK pathway after neuron damage. In light of the observed inhibitory effect of APPwt on JNKs, overactivation of the JNK signalling pathway in AD [44][45][46] might reflect a potential loss of the physiological function of APP. Parallel to this loss of function, enhanced Ab production might further enhance JNK activation, oxidative stress and mitochondrial dysfunction in AD.…”

Section: App Inhibits Uv-induced Jnk Activation and Cell Deathmentioning

confidence: 99%

Regulation of gene expression by the amyloid precursor protein: inhibition of the JNK/c-Jun pathway

et al. 2004

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The amyloid precursor protein (APP) has been suggested to regulate gene expression. GeneChip s analysis and in vitro kinase assays revealed potent APP-dependent repression of c-Jun, its target gene SPARC and reduced basal c-Jun Nterminal kinase (JNK) activity in PC12 cells overexpressing APP. UV-induced activation of the JNK signalling pathway and subsequent apoptosis were likewise reduced by APP and this effect could be mimicked by the indirect JNK inhibitor CEP-11004. Treatment with a c-secretase inhibitor did not affect APP-mediated downmodulation of the JNK signalling pathway, suggesting that the effects might be mediated via asecretase processing of APP. In support of these data, overexpression of the Swedish mutant of APP did not inhibit SPARC expression, UV-induced JNK activation and cell death. Our data suggest an important physiological role of APP and a-secretase activity in the control of JNK/c-Jun signalling, target gene expression and cell death activation in response to cytotoxic stress.

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JNK activation is associated with intracellular β-amyloid accumulation

Cited by 162 publications

References 49 publications

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

Heat Shock Protein 70 Participates in the Neuroprotective Response to Intracellularly Expressed β-Amyloid in Neurons

Regulation of gene expression by the amyloid precursor protein: inhibition of the JNK/c-Jun pathway

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