Login

Journal Image
Current Alzheimer Research
ISSN (Print): 1567-2050
ISSN (Online): 1875-5828
VOLUME: 1
ISSUE: 1
DOI: 10.2174/1567205043480519









Recent Evidence Regarding a Role for Cdk5 Dysregulation in Alzheimers Disease

img
Author(s): E. A. Monaco III
Pages 33-38 (6)
Abstract:
Based on a growing literature, cyclin-dependent kinase 5 (Cdk5) has been implicated in the pathological processes that contribute to neurodegeneration in Alzheimers disease (AD). Cdk5 is ubiquitously expressed, but its activity is largely localized to post-mitotic neurons due to neuron-specific expression of its activators p35 and p39. Sufficient Cdk5 activity is critical to normal central nervous system development, as in its absence, neuronal migration and axonal path finding are deranged. Conversely, excessive and mislocalized Cdk5 activity appears to be detrimental to neuronal function. In fact, the pathological hallmarks of AD, β-amyloid aggregates and neurofibrillary tangles, have been linked to Cdk5-mediated neuronal death. In this model, β-amyloid is the toxic stimulus that disrupts intracellular calcium homeostasis, leading to activation of calpains, a family of calcium-dependent proteases. Calpain-mediated cleavage of p35, yields a truncated p25 fragment that possesses a longer ha lf-life, lacks the necessary sequence targeting it to membranes, but retains the capacity to activate Cdk5. The resulting excessive and mislocalized Cdk5 activity targets tau as a substrate for hyperphosphorylation, which is a prerequisite of paired helical filament (PHF) formation. A number of recent reports, utilizing diverse methods, lend further support to this model of AD neurodegeneration, and several strategies for combating Cdk5 dysregulation have even been devised. However, the study of Cdk5 in AD is not without controversy, and questions remain regarding its role in the pathology. Herein, the most recent findings regarding this model are reviewed.
Keywords:
Cdk5, cyclin-dependent kinase 5, neurodegeneration, hyperphosphorylation, amyloid
Affiliation:
Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, USA