JNK regulates APP cleavage and degradation in a model of Alzheimer's disease

Colombo, Alessio; Bastone, Antonio; Ploia, Cristina; Sclip, Alessandra; Salmona, Mario; Forloni, Gianluigi; Borsello, Tiziana

doi:10.1016/j.nbd.2008.12.014

Cited by 137 publications

(105 citation statements)

References 28 publications

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“…Our results demonstrated that the AICD-mediated degradation of the Notch1-IC protein occurs independently of GSK-3. The phosphorylation of AICD at T668 by JNK3 contributes to the neuronal degeneration inherent to Alzheimer's disease (AD) by regulating its translocation into the cytoplasm, amyloidogenic processing and destabilization of AICD (Chang et al, 2006;Colombo et al, 2009;Lee et al, 2003;Santos et al, 2010;Shin et al, 2007;Sodhi et al, 2008). For that reason, it was anticipated that JNK3 might function as a possible regulator for Notch1 signaling by the deregulation of AICD.…”

Section: Discussionmentioning

confidence: 78%

“…The phosphorylation of AICD at T668 by JNK3 regulates APP signaling by accumulation in the cytoplasm, amyloidogenic processing, and the destabilization of AICD (Chang et al, 2006;Colombo et al, 2009;Lee et al, 2003;Santos et al, 2010;Shin et al, 2007;Sodhi et al, 2008). We subsequently attempted to characterize the involvement of JNK3 in the regulation of Notch1 signaling by using a reporter assay.…”

Section: Phosphorylation Of Aicd By Jnk3 Is Required For the Suppressmentioning

confidence: 99%

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Regulation of Notch1 signaling by the APP intracellular domain facilitates degradation of the Notch1 intracellular domain and RBP-Jk

Kim

Ann

et al. 2011

Journal of Cell Science

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The Notch1 receptor is a crucial controller of cell fate decisions, and is also a key regulator of cell growth and differentiation in a variety of contexts. In this study, we have demonstrated that the APP intracellular domain (AICD) attenuates Notch1 signaling by accelerated degradation of the Notch1 intracellular domain (Notch1-IC) and RBP-Jk, through different degradation pathways. AICD suppresses Notch1 transcriptional activity by the dissociation of the Notch1-IC–RBP-Jk complex after processing by γ-secretase. Notch1-IC is capable of forming a trimeric complex with Fbw7 and AICD, and AICD enhances the protein degradation of Notch1-IC through an Fbw7-dependent proteasomal pathway. AICD downregulates the levels of RBP-Jk protein through the lysosomal pathway. AICD-mediated degradation is involved in the preferential degradation of non-phosphorylated RBP-Jk. Collectively, our results demonstrate that AICD functions as a negative regulator in Notch1 signaling through the promotion of Notch1-IC and RBP-Jk protein degradation.

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Section: Discussionmentioning

confidence: 78%

Section: Phosphorylation Of Aicd By Jnk3 Is Required For the Suppressmentioning

confidence: 99%

Regulation of Notch1 signaling by the APP intracellular domain facilitates degradation of the Notch1 intracellular domain and RBP-Jk

Kim

Ann

et al. 2011

Journal of Cell Science

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“…12 Previous studies implicating JNKs in the pathogenesis of Alzheimer disease have shown that JNKs, particularly JNK3, can phosphorylate APP, enhancing Ab production. 13,14 JNK activity can also raise BACE1 expression 15 and is detected in granulovacuolar degeneration. 16 Activated JNKs are increased in Alzheimer disease brains 17 as well as some upstream JNK activators, such as JKK1.…”

Section: J Psychiatry Neurosci 2015;40(3)mentioning

confidence: 99%

Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: links to cognitive decline

Gourmaud

Paquet

Dumurgier

et al. 2015

jpn

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“…JNK activation has been reported to regulate the phosphorylation of APP, leading to modulation of Ab levels (Colombo et al 2007;Colombo et al 2009), as well as to mediate the phosphorylation of tau protein in vitro (Yoshida et al 2004). Furthermore, the JNK pathway is shown activated in preclinical models of AD, including Tg2576 and Tg575/PS1 P264L transgenic mice (Flood et al 2002;Puig et al 2004), as well as in brains of AD patients (Zhu et al 2003a;Zhu et al 2003b;Lagalwar et al 2006).…”

Section: Ab Production Is a Major Link Between Oxidative Stress And Pmentioning

confidence: 99%

Amyloid-β Production: Major Link Between Oxidative Stress and BACE1

et al. 2011

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Sequential endoproteolytic cleavages operated by the c-secretase and the b-secretase (BACE1) on the b-amyloid precursor protein result in the production of the b-amyloid (Ab) species, with two C-terminal variants, at residue 40 or at residue 42. Accumulation in brain tissue of aggregates of Ab42 is the major pathogenetic event in Alzheimer's disease (AD). The causes of Ab accumulation in the common sporadic form of AD are not completely understood, but they are likely to include oxidative stress (OS). Data reviewed here shed light on how Ab generation, oxidative stress, and secretase functions are intimately related in sporadic AD. According to our hypothesis, in sporadic AD, OS resulted from several cellular insults such as aging, hypoxia, hyperglycemia, and hypercholesterolemia-that are well-known risk factors for AD development-can determine a primary induction of c-secretase and BACE1. The loop proceeds with the generation of Ab42 and its signaling to BACE1 transcription.

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JNK regulates APP cleavage and degradation in a model of Alzheimer's disease

Cited by 137 publications

References 28 publications

Regulation of Notch1 signaling by the APP intracellular domain facilitates degradation of the Notch1 intracellular domain and RBP-Jk

Regulation of Notch1 signaling by the APP intracellular domain facilitates degradation of the Notch1 intracellular domain and RBP-Jk

Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: links to cognitive decline

Amyloid-β Production: Major Link Between Oxidative Stress and BACE1

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