Cdk5 deregulation in the pathogenesis of Alzheimer's disease

Cruz, Jonathan C.; Tsai, Li‐Huei

doi:10.1016/j.molmed.2004.07.001

Cited by 228 publications

(191 citation statements)

References 71 publications

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“…Similarly, partial TrkA mRNA silencing paradoxically favored neuronal survival, suggesting that the NGF receptor may switch from pro-survival to pro-apoptotic action in the absence of its specific ligand. In addition, pharmacological inhibition of Cdk and Src kinases, known to trigger amyloidogenesis by affecting APP phosphorylation and processing, [69][70][71][72] reduced the TrkA and PLCg phosphorylation levels and rescued neuronal cultures from death. Relevantly, in p75-silenced neurons, TrkA did not appear phosphorylated after NGF removal and the interruption of the amyloidogenic pathway was prevented.…”

Section: Ngf-deprived Hippocampal Neurons: the Amyloid Cascade And Tamentioning

confidence: 99%

Does the term ‘trophic’ actually mean anti-amyloidogenic? The case of NGF

et al. 2010

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Section: Ngf-deprived Hippocampal Neurons: the Amyloid Cascade And Tamentioning

confidence: 99%

Does the term ‘trophic’ actually mean anti-amyloidogenic? The case of NGF

et al. 2010

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“…It is widely recognized that several kinases, such as CDK5 and Src proteins, trigger amyloidogenesis by affecting APP phosphorylation and processing (7)(8)(9)20). It is also known that the Src family is involved in NGF-independent mechanism leading to TrkA phosphorylation (21).…”

Section: Cdk5 and Src Family Are Involved In Ptrka-mediated Neuronal mentioning

confidence: 99%

“…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)(8)(9), and by TrkA and p75 silencing.…”

mentioning

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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“…However, unlike those cell cycle Cdk5, the kinase activity of Cdk5 is detected mainly in post mitotic neurons. This is because Cdk5 activators p35 and p39 are expressed predominantly in neurons (13,14). The amount of p35 is the major determinant of Cdk5 activity, and it is normally a short-lived protein degraded by the ubiquitin-proteasome pathway (15,16).…”

Section: Parkinson Disease (Pd)mentioning

confidence: 99%