Pharmacological relevance of CDK inhibitors in Alzheimer's disease.

Nishtha Malhotra, Rohan Gupta, Pravir Kumar

Neurochemistry international 2021 Sep

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Evidence suggests that cell cycle activation plays a role in the pathophysiology of neurodegenerative diseases. Alzheimer's disease is a progressive, terminal neurodegenerative disease that affects memory and other important mental functions. Intracellular deposition of Tau protein, a hyperphosphorylated form of a microtubule-associated protein, and extracellular aggregation of Amyloid β protein, which manifests as neurofibrillary tangles (NFT) and senile plaques, respectively, characterize this condition. In recent years, however, several studies have concluded that cell cycle re-entry is one of the key causes of neuronal death in the pathogenesis of Alzheimer's disease. The eukaryotic cell cycle is well-coordinated machinery that performs critical functions in cell replenishment, such as DNA replication, cell creation, repair, and the birth of new daughter cells from the mother cell. The complex interplay between the levels of various cyclins and cyclin-dependent kinases (CDKs) at different checkpoints is needed for cell cycle synchronization. CDKIs (cyclin-dependent kinase inhibitors) prevent cyclin degradation and CDK inactivation. Different external and internal factors regulate them differently, and they have different tissue expression and developmental functions. The checkpoints ensure that the previous step is completed correctly before starting the new cell cycle phase, and they protect against the transfer of defects to the daughter cells. Due to the development of more selective and potent ATP-competitive CDK inhibitors, CDK inhibitors appear to be on the verge of having a clinical impact. This avenue is likely to yield new and effective medicines for the treatment of cancer and other neurodegenerative diseases. These new methods for recognizing CDK inhibitors may be used to create non-ATP-competitive agents that target CDK4, CDK5, and other CDKs that have been recognized as important therapeutic targets in Alzheimer's disease treatment. Copyright © 2021 Elsevier Ltd. All rights reserved.

Citation

Nishtha Malhotra, Rohan Gupta, Pravir Kumar. Pharmacological relevance of CDK inhibitors in Alzheimer's disease. Neurochemistry international. 2021 Sep;148:105115