These findings suggest that S-nitrosylation of Cdk5 is an aberrant regulatory mechanism of enzyme activity that may contribute to the pathogenesis of AD.
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.
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).
Experiments have shown that the peptide p5 reduces the CDK5-p25 activity without affecting the endogenous CDK5-p35 activity, whereas the peptide TFP5, obtained from p5, elicits similar inhibition, crosses the blood-brain barrier, and exhibits behavioral rescue of AD mice models with no toxic side effects.
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.
This article also highlights Drp1 and its relationships to glycogen synthase kinase 3, cyclin-dependent kinase 5, p53, and microRNAs in AD pathogenesis.
Egr-1 regulates tau phosphorylation and Aβ synthesis in the brain by respectively controlling activities of Cdk5 and BACE-1, suggesting that Egr-1 is a potential therapeutic candidate for the treatment of AD.
The hyperactivity of the cyclin-dependent protein kinase CDK5, involved in the development and differentiation of the nervous system, is associated with Alzheimer's disease.
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.
Subsequently, rescue experiments revealed that miR-125b induced neuron apoptosis, inhibited neurite outgrowth and promoted inflammation, also increased PTGS2 and CDK5 expressions but decreased FOXQ1 expression in lnc-MALAT1 overexpression treated AD models.
The p35/CDK5 active complex plays a fundamental role in brain development and functioning, but its deregulated activity has also been implicated in various neurodegenerative disorders, including Alzheimer's disease (AD).
Our results provide direct evidence that p35/p25-mediated cdk5 deregulation is not essential for NPC pathology and suggest that similar pathology in AD may also be cdk5 independent.
The calpain-mediated cleavage of p35 to p25 and the resulting aberrant activity and neurotoxicity of Cdk5 have been implicated in neurological disorders, such as Alzheimer's disease.
Still, additional studies using different sets of patients and control subjects deserve further attention, since supporting evidence for association between CDK5 gene and AD risk in the Dutch population exists.
This will include discussion of the evidence for increased GSK3 or Cdk5 activity, for decreased phosphatase activity, or the upregulation of other CRMP2 protein kinases in AD.
Our data are indicative for a role of the CDK5 molecular complex in the genetic etiology of early-onset AD, and suggest that a yet unknown functional variant in CDK5 or in a nearby gene might lead to increased susceptibility for early-onset AD.
Previously, we have demonstrated that adeno-associated virus serotype-9 (AAV9) mediated Cdk5 inhibitory peptide (CIP) inhibits the activity of Cdk5/p25 complex and alleviates pathologic and behavioral changes in Alzheimer's disease mouse model.
Importantly, increasing evidence has linked Cdk5 to the etiopathology of neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis.
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.