CDK5: The Connection Between Alzheimer's Disease and Type 2 Diabetes?

Abstract

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are two of the fastest growing diseases in the United States. T2DM is a complex, onset disorder arising from pancreatic beta cell failure and often associated with altered sensitivity of target tissues to insulin. AD is a neurodegenerative disorder causing a decline in cognitive ability, that is associated with two neuropathological hallmarks: neurofibrillary tangles (NFTs) comprised of hyperphosphorylated tau; and plaques comprised of aggregated amyloid beta proteins. Recent evidence suggests that insulin deregulation in the brain may play a role in the pathology of AD. Cyclin dependent kinase 5 (CDK5) is an unusual member of the cyclin dependent kinase family, because instead of a role in the cell cycle, it is predominately active in terminally differentiated neurons. CDK5 has been shown to be required for proper central nervous system development and for neuronal patterning and migration. Aberrant activation of CDK5 has been implicated in several neurodegenerative diseases, including AD, where its deregulation contributes to the formation of NFTs, among other protein aggregation and misfolding events. In addition to its role in neuronal development, CDK5 has also recently been associated with insulin exocytosis in the pancreas. An emerging correlation between TIIDM and AD suggests a connection between insulin deregulation and neurodegeneration. Because CDK5 is active in both tissues, it represents a possible common feature in these two pathologies. To study this connection, our lab uses the neuronal cell line model, PC12 which we transdifferentiate using neurotrophic growth factors. Once differentiated, we assess the extent of differentiation via qualitative and quantitative methods in the presence or absence of CDK5 chemical inhibitors and quantify the morphological changes using digital photomicroscopy. Our results indicate that aberrant CDK5 activity contributes to alterations in neuronal architecture. These along with changes in CDK5's kinase activity, confirms the effectiveness of our chemical inhibitors in altering CDK5 activity. Using this model, we have now begun to examine the role of normal and aberrant CDK5 activity on the response of differentiated neuronal‐like PC12 cells to varying concentrations of glucose and insulin in culture. Since a number of reports suggest that dysfunction in cerebral glucose metabolism and deregulation of brain insulin signaling are early abnormalities in AD, this model system provides a means to examine the potential role of CDK5 as a link between AD and Type II diabetes.Support or Funding InformationMarymount Manhattan College Faculty Research AwardSister Collette Mahoney Science Research GrantBadgeley FoundationJoseph A. Alexander FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.