MOLECULAR MECHANISMS IN P25/CDK5-MEDIATED NEUROINFLAMMATION AND SUBSEQUENT NEURODEGENERATION: THERAPEUTIC IMPLICATIONS FOR ALZHEIMER'S DISEASE

Abstract

Deregulation of Cyclin-dependent kinase 5 (Cdk5) by its truncated activator p25, is involved in tau and amyloid pathology found particularly in Alzheimer¿s disease (AD). Although, neuroinflammation is recognized as a prominent feature of AD pathology, the precise mechanism behind neuroinflammation and its significance in the initiation of neurodegeneration has not been fully elucidated. Hence, this study aims to address these knowledge gaps using in vitro p25 overexpressing neurons and to translate this in vivo in the p25 transgenic mouse. Results identified that cytosolic phospholipase 2 (cPLA2)-mediated production of lysophosphatidylcholine (LPC) is crucial for the initiation of p25-mediated neuroinflammation and the progression of neurodegeneration. Moreover, curcumin, a potent natural anti-inflammatory agent efficiently inhibited p25-mediated neuroinflammation as well as the progression of neurodegeneration in p25 transgenic mice. Together, data from this study will unveil potential therapeutic targets via inhibition of neuroinflammation in an AD paradigm for an effective treatment of the disease.