Cdk5 acts as a mediator of neuronal cell cycle re-entry triggered by amyloid-β and prion peptides

Lopes, João Pedro; Oliveira, Catarina R.; Agostinho, Paula

doi:10.4161/cc.8.1.7506

Cited by 68 publications

(63 citation statements)

References 48 publications

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“…In addition to active Cdc25 and Cdks, ectopic upregulation of Cdk1, Cdk4, phosphopRb, Cyclin B, Cyclin D, proliferating cell nuclear antigen (PCNA), Histone H3 (pSer10) and Plk have been reported in AD neurons (Nagy et al, 1997a;Nagy et al, 1997b;Busser et al, 1998;McShea et al, 1997;Thakur et al, 2008;Ding et al, 2000;Vincent et al, 2001;Ogawa et al, 2003;Harris et al, 2000). Studies from cultured cortical neurons and AD mouse models further demonstrate that Ab induces the activation or the levels of DNA polymerase-b, Cdk4, pRb, PCNA (Copani et al, 2006;Lopes et al, 2009;Varvel et al, 2008); however, the mechanism remains unclear.…”

Section: Discussionmentioning

confidence: 96%

Deregulated Cdk5 Triggers Aberrant Activation of Cell Cycle Kinases and Phosphatases Inducing Neuronal Death

Chang

Vincent

Shah

2012

Journal of Cell Science

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SummaryAberrant activation of cell cycle proteins is believed to play a critical role in Alzheimer's disease (AD) pathogenesis; although, the molecular mechanisms leading to their activation in diseased neurons remain elusive. The goal of this study was to investigate the mechanistic link between Cdk5 deregulation and cell cycle re-activation in b-amyloid 1-42 (Ab )-induced neurotoxicity. Using a chemical genetic approach, we identified Cdc25A, Cdc25B and Cdc25C as direct Cdk5 substrates in mouse brain lysates. We show that deregulated Cdk5 directly phosphorylates Cdc25A, Cdc25B and Cdc25C at multiple sites, which not only increases their phosphatase activities but also facilitates their release from 14-3-3 inhibitory binding. -treated primary cortical neurons, emphasizing a major role of Cdk5 in the activation of Cdc25 isoforms and Cdks in AD pathogenesis. These results were further confirmed in human AD clinical samples, which had higher Cdc25A, Cdc25B and Cdc25C activities that were coincident with increased Cdk5 activity, as compared to age-matched controls. Inhibition of Cdk5 confers the highest neuroprotection against Ab 1-42 toxicity, whereas inhibition of Cdc25 isoforms was partially neuroprotective, further emphasizing a decisive role of Cdk5 deregulation in cell-cycle-driven AD neuronal death.

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Section: Discussionmentioning

confidence: 96%

Deregulated Cdk5 Triggers Aberrant Activation of Cell Cycle Kinases and Phosphatases Inducing Neuronal Death

Chang

Vincent

Shah

2012

Journal of Cell Science

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“…[30][31][32] It is also reported that β amyloid protein and Cdk5 activity synergize to induce neuronal cell death, 33 and cell cycle re-entry underlies this phenomena. 34 It is now becoming more evident that cell cycle re-entry and cell death of neurons are closely linked to each other, although the mechanism is not clear. 35 In human neurodegenerative diseases, including Alzheimer disease (AD) and Parkinson disease (PD), ectopic expression of cell cycle-related proteins is reported.…”

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confidence: 99%

Cyclin-dependent kinase 5 regulates E2F transcription factor through phosphorylation of Rb protein in neurons

et al. 2012

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“…Hence, cells that are metabolically impaired reduce less MTT than "healthy cells". 56,57 The phenoxyalkylamino-4-phenylnicotinates (2−7) and phenoxyalkoxybenzylidenemalononitriles 12,13 ( Figure 3A), and pyridonepezils (14−18) and pyrazolo [3,4-b]quinolines (35−37) ( Figure 3B) were assessed. The data obtained show that these sets of compounds did not significantly affect neuronal viability for concentrations up to 5 μM, whereas for higher concentrations the compounds affected the neuronal viability by 15% or more.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Synthesis, Pharmacological Assessment, and Molecular Modeling of Acetylcholinesterase/Butyrylcholinesterase Inhibitors: Effect against Amyloid-β-Induced Neurotoxicity

Silva

Chioua

Samadi

et al. 2013

ACS Chem. Neurosci.

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ABSTRACT:The synthesis, molecular modeling, and pharmacological analysis of phenoxyalkylamino-4-phenylnicotinates (2−7), phenoxyalkoxybenzylidenemalononitriles (12, 13), pyridonepezils (14−18), and quinolinodonepezils (19−21) are described. Pyridonepezils 15−18 were found to be selective and moderately potent regarding the inhibition of hAChE, whereas quinolinodonepezils 19−21 were found to be poor inhibitors of hAChE. The most potent and selective hAChE inhibitor was ethyl 6-(4-(1-benzylpiperidin-4-yl)butylamino)-5-cyano-2-methyl-4-phenylnicotinate (18) [IC 50 (hAChE) = 0.25 ± 0.02 μM]. Pyridonepezils 15−18 and quinolinodonepezils 20−21 are more potent selective inhibitors of EeAChE than hAChE. The most potent and selective EeAChE inhibitor was ethyl 6-(2-(1-benzylpiperidin-4-yl)ethylamino)-5-cyano-2-methyl-4-phenylnicotinate (16) [IC 50 (EeAChE) = 0.0167 ± 0.0002 μM], which exhibits the same inhibitory potency as donepezil against hAChE. Compounds 2, 7, 13, 17, 18, 35, and 36 significantly prevented the decrease in cell viability caused by Aβ 1−42 . All compounds were effective in preventing the enhancement of AChE activity induced by Aβ 1−42 . Compounds 2−7 caused a significant reduction whereas pyridonepezils 17 and 18, and compound 16 also showed some activity . The pyrazolo [3,4-b]quinolines 36 and 38 also prevented the upregulation of AChE induced by Aβ 1−42 . Compounds 2, 7, 12, 13, 17, 18, and 36 may act as antagonists of voltage sensitive calcium channels, since they significantly prevented the Ca 2+ influx evoked by KCl depolarization. Docking studies show that compounds 16 and 18 adopted different orientations and conformations inside the active-site gorges of hAChE and hBuChE. The structural and energetic features of the 16-AChE and 18-AChE complexes compared to the 16-BuChE and 18-BuChE complexes account for a higher affinity of the ligand toward AChE. The present data indicate that compounds 2, 7, 17, 18, and 36 may represent attractive multipotent molecules for the potential treatment of Alzheimer's disease.

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Cdk5 acts as a mediator of neuronal cell cycle re-entry triggered by amyloid-β and prion peptides

Cited by 68 publications

References 48 publications

Deregulated Cdk5 Triggers Aberrant Activation of Cell Cycle Kinases and Phosphatases Inducing Neuronal Death

Deregulated Cdk5 Triggers Aberrant Activation of Cell Cycle Kinases and Phosphatases Inducing Neuronal Death

Cyclin-dependent kinase 5 regulates E2F transcription factor through phosphorylation of Rb protein in neurons

Synthesis, Pharmacological Assessment, and Molecular Modeling of Acetylcholinesterase/Butyrylcholinesterase Inhibitors: Effect against Amyloid-β-Induced Neurotoxicity

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