Identification of Novel Mechanisms in Alzheimer's Pathogenesis and Progression

Project Summary

Our goal is to study the role of death-associated protein kinase 1 (DAPK1) in Alzheimer’s disease (AD) using mouse models and to determine the relationship between DAPK1 and neuronal cell death in human AD.
 
Neuronal cell death plays an essential role in normal physiology for a biological process, however, when impaired or influenced by various factors, it may contribute to neurodegenerative disorders, including AD. Recent studies have shown that DAPK1 might have a critical role in AD. We recently discovered that DAPK1 expression is markedly increased in 75 percent of human AD patient brains.  Moreover, we showed that DAPK1 regulates two major AD-related molecules: tau and amyloid precursor protein (APP). We have identified novel DAPK1 substrates that are involved in neuronal cell death and AD including N-myc downstream-regulated gene 2 (NDRG2). Thus, this proposal is designed to test our novel hypothesis that DAPK1 is a critical regulator in neuronal cell death and its deregulation, in the face of additional stresses, might contribute to the development of AD. We will first examine whether DAPK1 regulates neuronal cell death by affecting potential DAPK1 substrates and determine the novel molecular pathway by which DAPK1 regulates neuronal cell death. Next, we will examine neuronal cell death in vivo using novel animal models to determine the relationship between DAPK1 and neuronal loss. This study would provide novel insights into the critical mechanisms of DAPK1 in neuronal cell death and the development of AD, and provide a novel therapeutic option for AD treatments.