7-bromoindirubin-3-oxime (7Bio), an indirubin derivative derived from indirubin-3-oxime, possesses inhibitory effects against cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3β (GSK3β), two pharmacological targets of Alzheimer's disease (AD).
Cdk5 phosphorylates tau at AD-specific phospho-epitopes when it associates with p25. p25 is a truncated activator, which is produced from the physiological Cdk5 activator p35 upon exposure to Abeta peptides.
Cdk5 activity becomes deregulated in various brain disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, attention-deficit hyperactivity disorder, epilepsy, schizophrenia, and ischemic stroke; these all result in profound remodeling of the neuronal cytoskeleton.
Cdk5 activity is deregulated in various brain disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and ischemic stroke, resulting in profound remodeling of the neuronal cytoskeleton, loss of synapses, and ultimately neurodegeneration.
A number of signaling proteins, including fyn kinase; glycogen synthase kinase-3beta (GSK3beta) and cyclin-dependent kinase-5 (CDK5), are involved in the neurodegenerative progression of AD.
Although aberrant Cdk5 activity mediated by Cdk5/p25 is suggested to promote Aβ plaque deposition, the effects of Cdk5 inhibition on Aβ plaque loads in AD mouse models have been equivocal, possibly due to the fact that Cdk5 can be activated by p35 or p39 and their cleaved products.
Although the function of MGMT, parkin, ApoD, PAR-4, and Cdk5 was previously known in AD, the findings presented here provide novel evidence of the significance of CSF analysis in the mapping of the AD pathomechanism.
As an example, we experimentally quantified the function of the kinase Cdk5, an enzyme implicated in Alzheimer's disease, at concentrations that are 5-fold lower than physiological values, and with sufficient time-resolution to allow the estimation of both steady-state and kinetic parameters in a single experiment.
Certain factors contribute to the aetiogenesis of AD by regulating insulin signaling pathway in the brain and accelerating the formation of neurotoxic Aβ and NFTs via various mechanisms, including GSK3β, JNK, CamKII, CDK5, CK1, MARK4, PLK2, Syk, DYRK1A, PPP, and P70S6K.
Collectively, these findings recommend that two compounds have great potential to be a promising agent against AD to reduce the CDK5 induced hyperphosphorylation and could be considered as therapeutic agents for the AD.Communicated by Ramaswamy H. Sarma.
Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment.
Contrary to cell cycle-associated cyclin-dependent kinases, CDK5 is best known for its regulation of signaling processes in differentiated cells and its destructive activation in Alzheimer's disease.
Cortex from 13 AD patients immunized with AN1792 (iAD) and from 27 nonimmunized AD (cAD) cases was immunolabeled for proapoptotic proteins implicated in AD pathophysiology: phosphorylated c-Jun N-terminal kinase (pJNK), activated caspase3 (a-casp3), phosphorylated GSK3β on tyrosine 216 (GSK3β<sub>tyr216</sub> ), p53 and Cdk5/p35.
Deregulated Cdk5 causes neurotoxic amyloid beta peptide (Aβ) processing and cell death, two hallmarks of Alzheimer's disease, through the Foxo3 transcriptional factor in hippocampal cells, primary neurons and an Alzheimer's disease mouse model.
Deregulation of Cdk5 has been implicated in Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease and acute neuronal injury.
Deregulation of Cyclin-dependent kinase 5 (Cdk5) activity by production of its hyperactivator p25 is involved in the formation of tau and amyloid pathology reminiscent of Alzheimer's disease (AD).
Deregulation of Cyclin-dependent kinase 5 (CDK5) by binding to the activated calpain product p25, is associated with the onset of neurodegenerative diseases, such as Alzheimer's disease (AD).
Dysfunction of Cdk5 has been implicated in a number of neurological disorders and neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Niemann-Pick type C disease, and ischemia.