The role of complement anaphylatoxin C5a in neurodegeneration: implications in Alzheimer's disease.
There is evidence that the complement system, a major component of inflammatory responses, may play an important role in neurodegenerative conditions such as Alzheimer's disease (AD). Work from our lab demonstrated that mice genetically deficient in the complement component C5 are more susceptible to hippocampal excitotoxic lesions (Pasinetti et al., 1996) and that the C5-derived ana;hylatoxin C5a may protect against excitotoxicity in vitro and in vivo (Osaka et al., 1999). Potential mechanisms identified in C5a-mediated neuroprotection include activation of mitogen activated protein (MAP)-kinase (Osaka et al., 1998; Osaka et al., 1999). This novel neuroprotective role of C5a complicates current theories that complement proteins augment beta-amyloid (Abeta) toxicity in AD. In view of the fact that the complement system represents a target for therapeutic interventions in AD, further characterization of the complex role of complement proteins is essential. Towards this aim, we have characterized a transgenic C5a receptor (C5aR) knockout (KO) mouse. Recent studies in the lab using C5aR-KO mice show that disruption of C5aR alters calcium calmodulin kinase (CaM-KII) signal transduction in brain cells. We are presently using C5aR-KO mice to study the role of C5a in caspase mediated apoptotic neuronal death. In this review we will attempt to delineate possible neuroprotective roles for C5a in mechanisms of neurotoxicity pertaining to AD.
Mukherjee
P
P
Neuroinflammation Research Center of the Department of Psychiatry, The Mount Sinai School of Medicine, One Gustave, L. Levy Place, Brookdale Center for Molecular Biology, New York, NY 100129-6574, USA.
Pasinetti
G M
GM
D000544:Alzheimer Disease / Q000209:etiology*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D020169:Caspases / Q000502:physiology; D015936:Complement C5a / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology
D015936:Complement C5a; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases