In Vitro Phosphorylation of the Cytoplasmic Domain of the Amyloid Precursor Protein by Glycogen Synthase Kinase‐3β

Ae, Aplin; Gm, Gibb; Js, Jacobsen; Gallo, Jean‐Marc; Bh, Anderton

doi:10.1046/j.1471-4159.1996.67020699.x

Cited by 177 publications

(104 citation statements)

References 29 publications

(38 reference statements)

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“…Phosphorylation of AICD at T668 influences AICD stability and leads to destabilization of AICD during differentiation of primary neurons in culture (Kimberly et al, 2005). Among the several kinases that have been described to phosphorylate APP at T668 (Suzuki et al, 1994;Aplin et al, 1996;Iijima et al, 2000;Taru and Suzuki, 2004;Kimberly et al, 2005), the c-Jun NH 2 -terminal kinase (JNK) seems to play an important role in vivo (Kimberly et al, 2005). JNK is a serine/threonine kinase, but it may be activated by pathways involving receptor tyrosine kinases, e.g., the PDGFR (Yu et al, 2003) and c-Kit (Hong et al, 2004), which can be inhibited by Gleevec.…”

Section: Discussionmentioning

confidence: 99%

Gleevec Increases Levels of the Amyloid Precursor Protein Intracellular Domain and of the Amyloid-β–degrading Enzyme Neprilysin

Eisele

Baumann²,

Klebl³

et al. 2007

MBoC

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Amyloid-␤ (A␤) deposition is a major pathological hallmark of Alzheimer's disease. Gleevec, a known tyrosine kinase inhibitor, has been shown to lower A␤ secretion, and it is considered a potential basis for novel therapies for Alzheimer's disease. Here, we show that Gleevec decreases A␤ levels without the inhibition of Notch cleavage by a mechanism distinct from ␥-secretase inhibition. Gleevec does not influence ␥-secretase activity in vitro; however, treatment of cell lines leads to a dose-dependent increase in the amyloid precursor protein intracellular domain (AICD), whereas secreted A␤ is decreased. This effect is observed even in presence of a potent ␥-secretase inhibitor, suggesting that Gleevec does not activate AICD generation but instead may slow down AICD turnover. Concomitant with the increase in AICD, Gleevec leads to elevated mRNA and protein levels of the A␤-degrading enzyme neprilysin, a potential target gene of AICDregulated transcription. Thus, the Gleevec mediated-increase in neprilysin expression may involve enhanced AICD signaling. The finding that Gleevec elevates neprilysin levels suggests that its A␤-lowering effect may be caused by increased A␤-degradation. INTRODUCTIONThe main neuropathological features of Alzheimer's disease (AD) are the extracellular deposition of amyloid-␤ (A␤) peptides and the formation of intracellular neurofibrillary tangles, accompanied by neuron loss and dementia (Selkoe, 2001). A␤ is generated by sequential proteolytic cleavages of the amyloid precursor protein (APP) by ␤-secretase (BACE) and ␥-secretase. The ␥-secretase cleavage occurs within the membrane, releasing the APP intracellular domain (AICD) into the cytosol. AICD, together with its binding partners Fe65 and Tip60, is considered to be involved in transcriptional regulation (Cao and Sudhof, 2001). Putative target genes of AICD signaling have been suggested (Baek et al., 2002;Kim et al., 2003;von Rotz et al., 2004;Pardossi-Piquard et al., 2005;Ryan and Pimplikar, 2005;Muller et al., 2007), although results for some of these genes are controversial (Hass and Yankner, 2005;Hebert et al., 2006;Chen and Selkoe, 2007;Pardossi-Piquard et al., 2007). One potential AICD target gene is the A␤-degrading enzyme neprilysin (Pardossi-Piquard et al., 2005, a metalloprotease that is one of the main A␤-degrading enzymes in the brain (Carson and Turner, 2002).␥-Secretase is a multiprotein complex, processing several type I integral membrane proteins, including APP and the Notch receptor (Kopan and Ilagan, 2004). Therapeutic strategies aimed at lowering A␤ include the development of selective ␥-secretase inhibitors (Evin et al., 2006). However, long-term treatment with ␥-secretase inhibitors has shown severe side effects in preclinical animal studies due to inhibition of Notch processing and signaling (Searfoss et al., 2003;Wong et al., 2004).Recently, Gleevec (signal transduction inhibitor 571, STI571, imantinib mesylate), a tyrosine kinase inhibitor, has been described to lower A␤ in a cell-free system, in N2A cells e...

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Section: Discussionmentioning

confidence: 99%

Gleevec Increases Levels of the Amyloid Precursor Protein Intracellular Domain and of the Amyloid-β–degrading Enzyme Neprilysin

Eisele

Baumann²,

Klebl³

et al. 2007

MBoC

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“…Both kinases phosphorylate tau at a large number of sites, most of which are common to the two enzymes (Wang et al, 1998;Anderton et al, 2001). Moreover, CDK5 and GSK3␤ are the key kinases responsible for the APP phosphorylation (Aplin et al, 1996;Iijima et al, 2000). Given the inhibitory role of ATRA in the phosphorylation of both tau and APP, we attempted to determine whether ATRA plays a role in regulating CDK5 and/or GSK3␤.…”

Section: Atra Prevents App Processing and Phosphorylation Of Both Appmentioning

confidence: 99%

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

Ding¹,

et al. 2008

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Recent studies have revealed that disruption of vitamin A signaling observed in Alzheimer's disease (AD) leads to ␤-amyloid (A␤) accumulation and memory deficits in rodents. The aim of the present study was to evaluate the therapeutic effect of all-trans retinoic acid (ATRA), an active metabolite of vitamin A, on the neuropathology and deficits of spatial learning and memory in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice, a well established AD mouse model. Here we report a robust decrease in brain A␤ deposition and tau phosphorylation in the blinded study of APP/PS1 transgenic mice treated intraperitoneally for 8 weeks with ATRA (20 mg/kg, three times weekly, initiated when the mice were 5 months old). This was accompanied by a significant decrease in the APP phosphorylation and processing. The activity of cyclin-dependent kinase 5, a major kinase involved in both APP and tau phosphorylation, was markedly downregulated by ATRA treatment. The ATRA-treated APP/PS1 mice showed decreased activation of microglia and astrocytes, attenuated neuronal degeneration, and improved spatial learning and memory compared with the vehicle-treated APP/ PS1 mice. These results support ATRA as an effective therapeutic agent for the prevention and treatment of AD.

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“…De plus, le lithium réduit l'agrégation Plaques séniles et peptide amyloïde La GSK-3 est impliquée dans la régulation du clivage protéolytique de l'APP (précurseur de la protéine amyloïde) et la production du peptide amyloïde (A ), un petit peptide toxique issu de coupures successives de l'APP par les sécrétases et principal constituant des plaques séniles. In vitro, la GSK-3 phosphoryle l'APP [5]. In vivo, dans des cerveaux de souris transgéniques surexprimant l'APP, l'inhibition de la GSK-3 par des inhibiteurs plus ou moins spécifiques, comme le lithium ou le valproate, diminue la production d'A et protège les neurones contre la toxicité du peptide [6,7].…”

Section: Potentiel Thérapeutique Des Inhibiteurs De Gsk-3bunclassified

GSK-3β : une kinase au cœur des maladies neuro-dégénératives ?

Petit-Paitel

2010

Med Sci (Paris)

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In Vitro Phosphorylation of the Cytoplasmic Domain of the Amyloid Precursor Protein by Glycogen Synthase Kinase‐3β

Cited by 177 publications

References 29 publications

Gleevec Increases Levels of the Amyloid Precursor Protein Intracellular Domain and of the Amyloid-β–degrading Enzyme Neprilysin

Gleevec Increases Levels of the Amyloid Precursor Protein Intracellular Domain and of the Amyloid-β–degrading Enzyme Neprilysin

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

GSK-3β : une kinase au cœur des maladies neuro-dégénératives ?

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