Amyloid β Binds Trimers as Well as Monomers of the 75-kDa Neurotrophin Receptor and Activates Receptor Signaling

Yaar, Mina; Zhai, Shengli; Fine, Richard E.; Eisenhauer, Patricia B.; Arble, Bennett L.; Stewart, Kenneth B.; Gilchrest, Barbara A.

doi:10.1074/jbc.m110929200

Cited by 149 publications

(148 citation statements)

References 38 publications

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“…55 One of the typical feature found in post-mortem studies on brains from AD patients is an overexpression of c-Jun, 56 which is also a hallmark of Ab-induced apoptosis in neuronal cultures. 17,44 This transcription factor was found to play a major role in Ab-induced neurotoxicity. 17,18 In the present study, we showed that the protective action of 12-LOX antisense oligonucleotide against Ab-mediated toxicity was associated with the suppression of c-Jun overexpression.…”

Section: Discussionmentioning

confidence: 99%

“…[40][41][42] Moreover, both c-Jun expression and activation were found to be increased following exposure of neurons to Ab, and recent data suggested a 12-Lipoxygenase and amyloid peptide toxicity A Lebeau et al critical role of this transcription factor in Ab-induced apoptosis. [17][18][19]43,44 We therefore investigated whether 12-LOX blockade could interfere with such an Ab-induced c-Jundependent apoptotic pathway in cortical cells.…”

Section: Blockade Of 12-lox Expression Disrupts a C-jun-dependent Ab-mentioning

confidence: 99%

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Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

et al. 2004

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The cyclo-oxygenase (COX) and lipoxygenase (LOX) pathways belong to the eicosanoid synthesis pathway, a major component of the chronic inflammatory process occurring in Alzheimer's disease (AD). Clinical studies reported beneficial effects of COX inhibitors, but little is known about the involvement of LOXs in AD pathogenesis. b-amyloid peptide (Ab) accumulation contributes to neurodegeneration in AD, but mechanisms underlying Ab toxicity have not been fully elucidated yet. Here, using an antisense oligonucleotide-based strategy, we show that blockade of 12-LOX expression prevents both Ab-induced apoptosis and overexpression of c-Jun, a factor required for the apoptotic process, in cortical neurons. Conversely, the 12-LOX metabolite, 12(S)-HETE (12(S)-hydroxy-(5Z, 8Z, 10E, 14Z)-eicosatetraenoic acid), promoted c-Jun-dependent apoptosis. Specificity of the 12-LOX involvement was further supported by the observed lack of contribution of 5-LOX in this process. These data indicate that blockade of 12-LOX expression disrupts a c-Jun-dependent apoptosis pathway, and suggest that 12-LOX may represent a new target for the treatment of AD.

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Section: Discussionmentioning

confidence: 99%

Section: Blockade Of 12-lox Expression Disrupts a C-jun-dependent Ab-mentioning

confidence: 99%

Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

et al. 2004

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“…An Abeta pathway, inducing TrkA phosphorylation directly by itself and indirectly by promoting NGF secretion (28), has recently been reported. p75 expression is also linked to changes occurring in AD (17,29), probably through its direct binding to Abeta 1-42 peptides (29,30). In addition, p75 mediates APP promoter activity, leading to an increase of secreted APP (31,32), and undergoes intramembrane ␣ and ␥ secretase-mediated processing to generate p75 CTF and p75 ICD fragments, respectively (11).…”

Section: Discussionmentioning

confidence: 99%

Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation

Matrone

Marolda

Ciafrè

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The present study shows that increased Abeta production in hippocampal neurons, due to a failure of NGF signal, induces an unexpected phosphorylation of tyrosine kinase receptor A (TrkA), followed by activation of the phospholipase C ␥ (PLC␥) pathway and neuronal death. Such phosphorylation seems causally connected with 2 kinases known be involved in amyloidogenesis, Src and CDK5, and associated with ␣ and ␥ secretase-mediated p75 processing. Pharmacologic inhibition of TrkA phosphorylation and partial silencing of TrkA and/or p75 receptors prevent PLC␥ activation and protect neurons from death. Concomitantly with these events, TrkA, p75, Abeta peptides, and PS1 protein coimmunoprecipitate, suggesting their direct interplay in the subsequent onset of apoptotic death. Together, these findings depict a cellular mechanism whereby the same cellular transducing system may invert its intracellular message from trophic and antiapoptotic to a death signaling, which could also have relevance in the onset of Alzheimer's disease.N GF mediates survival, differentiation, growth, and apoptosis of neurons by binding to 2 types of cell-surface receptors. Whereas tyrosine kinase receptor A (TrkA) has been shown to transduce specific prosurvival signals via an intricate network of intracellular pathways (1), the pan-p75 receptor (p75) modulates NGF affinity for TrkA and has been shown to be involved in transducing or directly carrying out death signals (2).Recently several articles have summarized evidence for a causal link between deficit in NGF signaling, transport, and processing and the onset of Alzheimer's disease (AD) (3,4).We have recently demonstrated that the interruption of NGF signaling in neurons activates the amyloidogenic pathway and induces death through a still-unclear mechanism (5, 6).Here we show that 24 h after NGF deprivation, TrkA undergoes an unexpected NGF-independent phosphorylation. This posttranslational modification is induced either by the overproduced pool of Abeta or by exogenously added Abeta and is strictly connected to neuronal death. Such TrkA phosphorylation is largely prevented by inhibitors of CDK5 and Src intracellular pathways, both involved in amyloid processing (7-9), and by TrkA and p75 silencing.Concomitantly with TrkA phosphorylation, the amounts of p75 C-terminal fragments, which are the products of ␣ and ␥ secretase cleavage on p75 (10, 11), increase and associate with TrkA to form a molecular complex also including a full length of p75, Abeta peptides, and PS1 protein.

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“…Localization of ADD, which has been more or less precisely determined depending on receptor, is indicated by double arrows. other cell-death-inducing ligands have been proposed for p75 NTR , such as pro-NGF (Lee et al, 2001b), b-amyloid (Yaar et al, 2002) and prion (Della-Bianca et al, 2001) peptides. The decision between ligandinduced apoptosis and ligand-inhibited apoptosis mediated by p75 NTR likely depends on cell type and development stage (Barrett and Bartlett, 1994).…”

Section: Dependence Receptors: a Short Historymentioning

confidence: 99%

Dependence receptors: a new paradigm in cell signaling and cancer therapy

2010

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Dependence receptors (DRs) now form a family of more than a dozen membrane receptors that are not linked by their structure, but by common functional traits. The most notable is their ability to trigger two opposite signaling pathways: in the presence of ligand, these receptors activate classic signaling pathways implicated in cell survival, migration and differentiation. In the absence of ligand, they do not stay inactive, rather they elicit an apoptotic signal. Thus, cells expressing this kind of receptor are dependent on the presence of ligand in the extracellular environment to survive. This review will recapitulate the increasing data regarding the molecular mechanisms associated with DRs, their potential implication during development, as well as their deregulation during tumorigenesis and, finally, their emergence as new possible therapeutic targets for cancer treatment.

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Amyloid β Binds Trimers as Well as Monomers of the 75-kDa Neurotrophin Receptor and Activates Receptor Signaling

Cited by 149 publications

References 38 publications

Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation

Dependence receptors: a new paradigm in cell signaling and cancer therapy

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