Investigating the Role of Cdk5 in Alzheimer's Disease and Type‐2 Diabetes
Authors: Furnari Julia Lynn , Aguanno Ann 
Published: June 2021

Alzheimer's disease (AD), a progressive, age‐related neurodegenerative disorder, affects more than 30 million people worldwide. The etiology of this disease remains unclear, although risks factors such as aging, type‐2 diabetes and obesity have been identified. Hallmarks of AD include extracellular amyloid‐b plaques and interneuronal neurofibrillary tangles of hyperphosphorylated tau protein. Our lab investigates the role of Cyclin dependent kinase 5 (Cdk5) in mammalian nervous system development using the well‐established neuronal cell model PC12. PC12 cells are derived pheochromcytoma of a rat adrenal medulla. Our early findings have shown that Cdk5 is essential for the establishment of crucial neuronal cell morphology and action. This is in good agreement with other published reports that show Cdk5 is required for proper central nervous system development and for neuronal patterning and migration. Given Cdk5's role in neuronal development and that one of its substrates is tau, we decided to explore a role for Cdk5 in neurodegeneration. Chemical inhibition of Cdk5 revealed extreme aberrations in nerve cell morphology, architecture and function in our PC12 cell line in the presence of neurotrophic factors. To characterize and quantify these physical changes, we devised a simple method to convert these qualitative results to quantitative results, allowing rigorous comparison of our data. Our findings align well with the reports of other labs demonstrating a role for Cdk5 in the formation of neurofibrillary tangles and other protein aggregation and misfolding events in neurodegenerative diseases like AD. Cdk5 has also been implicated in the differentiation of extra neural tissues, including the pancreas. Since some of the risk factors for AD includes obesity and Type 2 diabetes, we also investigated the effect of Cdk5 inhibition in pancreatic cell models. Our findings suggest a role for Cdk5 in insulin secretion, supporting published reports of a role for Cdk5 in exocytosis in the pancreas. Recent evidence that deregulation of brain insulin plays a role in the pathology of AD may explain the associated risk factors of obesity and Type 2 diabetes with AD. Therefore, we are exploring the neuronal phenotype under hyperglycemic conditions while manipulating Cdk5 activity. We are extending our research using another well‐known neuronal cell model, N2a, a murine neuroblastoma. Here we report our test results of the impact of normal and aberrant Cdk5 activity on the response of differentiated N2a cells to varying concentrations of glucose in culture. This has allowed us to draw broader conclusions regarding the role of Cdk5 in neuronal development and degeneration and the connection between type II diabetes and AD. Since a number of reports suggest that dysfunction in cerebral glucose metabolism 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 Information

The Rose M. Badgely Charitable Trust, Joseph Alexander Foundation, Sister Colette Mahoney Science Research Grant and the Marymount Manhattan College Faculty Award.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.