Roles of Inducible Inflammatory Proteins in Neurodegenerative Diseases (I)

Neuroinflammation is a hallmark of all major CNS neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson’s disease (PD). The elevated expression of various inflammatory proteins such as adhesion molecules, cyclooxygenase enzymes and their products, cytokines, and proteases (MMPs) in experimental and clinical neurodegenerative disease, and intervention studies in experimental animals suggest that several of these factors contribute to neuronal injury. Most notably, cytokines (IL-1 and TNF-), endotoxins, oxidized LDL, and bradykinin have been implicated in neurodegeneration. In spite of their diverse presentation, common inflammatory mechanisms underlying the expression of these inflammatory proteins may contribute to tissue remodeling and neurodegenerative progress. Recently, oxidative stress due to generation of ROS (e.g. mitochondrial dysfunction and NADPH oxidase activation) may be involved in brain injury and inflammation. ROS can also be sensed by the cells and trigger intracellular signaling cascades potentiating chronic inflammation. Interplay between ROS and inflammatory proteins induced by proinflammatory mediators leading to neurodegeneration remains largely unknown. Moreover, we have demonstrated that IL-1 and bradykinin (BK) may act as pro-inflammatory factors and induce expression of cPLA2, COX-2 and matrix metalloproteinase-9 (MMP-9). MMPs may change the BBB function in various brain injuries and neuroinflammation. Therefore, we hypothesize that the proinflammatory mediators-initiated neurodegeneration is mediated by the generation of ROS and the induction of inflammatory proteins (MMPs, COX-2 or iNOS) in brain cells (i.e. glial cells and neuronal cells). To test this hypothesis, this proposal will investigate the molecular mechanisms underlying proinflammatory factors (including five categories: IL-1, BK, lipoteichoic acid (LTA), oxLDL, and TGF-1) regulated expression of MMPs, PLA2, COX-2 or iNOS in astrocytes, including (1) to evaluate whether the expression of inflammatory mediators induced by proinflammatory factors, (2) to characterize the role of ROS in expression of inflammatory mediators induced by proinflammatory factors, (3) to determine whether activation of MAPKs (e.g. ERK, p38 MAPK, and JNK) by proinflammatory factors leading to expression of inflammatory mediators, (4) to differentiate whether alternative pathways (RTK and PI3K/Akt transactivation) involved in expression of inflammatory mediators induced by proinflammatory factors, (5) to characterize the roles of various transcription factors and coactivators in expression of inflammatory mediators induced by proinflammatory factors, and (6) to evaluate the roles of these upregulated inflammatory mediators on astrocytic or neuronal physiological and pathological functions in vitro and in vivo studies. These experiments should provide new insights into the mechanisms involved in neuroinflammation and neurodegeneration. Increased understanding of these mechanisms underlying up-regulation of these genes will create opportunities for the development of therapeutic strategies in neurodegenerative diseases.

Project ID:PC9712-0464
External Project ID:NSC97-2321-B182-007