The role of complement anaphylatoxin C5a in neurodegeneration: implications in Alzheimer’s disease

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Abstract

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 β-amyloid (Aβ) 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.

Section snippets

Complement anaphylatoxin C5a is generated through the activation of C5

The complement system is a major mediator of inflammatory responses that has been studied far less in the brain than other organs. Composed of more than 25 proteins, the complement system is activated most commonly by antigen-antibody complexes but also by other molecules found in brain, for example myelin and neurofilaments (reviewed in Pasinetti, 1996). In general, activated complement components have multiple roles including enhancement of phagocytosis (opsonization), chemotaxis to guide the

C5a and its role in mechanisms of neurodegeneration

We have used mice genetically deficient of C5 to study the role of this complement component in neurodegenerative mechanisms. Surprisingly, C5-deficient mice show more neuronal injury to kainic acid (KA) excitotoxicity (Pasinetti et al., 1996; Tocco et al., 1997). These studies suggested that in addition to their contribution to degenerative mechanisms, specific complement components may mediate neuroprotection. This hypothesis was further supported by the recent evidence showing that human

Generation of C5a anaphylatoxin in the brain

Little is known about the generation of C5a and other anaphylatoxins in the brain. We have evidence that C5 mRNA is locally expressed in the mouse brain (Osaka et al., 1998). Also, C5a can be generated proteolytically from C5 even in the absence of classical complement activation, as found in periodontal diseases (Wingrove et al., 1982) or by non-complement related enzymes like trypsin, a-thrombin, elastase and cathespin (Wetsel and Kolb, 1983). Therefore, it is plausible that in lesioned (and

The role of complement in neurodegeneration and AD

Demonstration of complement activation in the AD brain has caused much speculation regarding the role of such inflammatory cascades in neurodegenerative mechanisms (Pasinetti, 1996; Lampert-Etchells et al., 1993). There is evidence that complement proteins can augment aspects of Aβ neurotoxicity. For example, recent studies suggest that the interaction of C1q (the first component of the complement cascade) with Aβ peptides not only increases the aggregability and toxicity of Aβ (Jiang et al.,

Ca2+/calmodulin-dependent (CaM-KII) protein kinase: a novel target for modulation of C5aR-mediated responses

Recent evidence from the lab indicates that hrC5a mediated neuroprotection may be exerted, in part, through mechanisms which involve modulation of CAM-KII signal transduction. The multifunctional CAM-KII is a well known effector of Ca2+ and calmodulin related functions. CAM-KII is present in many tissues (including an abundance in the brain) and has broad substrate specificity. These characteristics suggest CAM-KII may play a role in many cellular functions (reviewed in Hanson and Schulman, 1992

Role of C5a on regulation of MAP-kinase

Since MAP kinases play an important role in mechanisms of cell death/survival as well as chemotaxis in circulating inflammatory cells, we explored the role of C5a on the activation of MAP-ERK in the brain. MAP-ERK kinase has widespread distribution as a family of serine/threonine protein kinases and is activated in response to stimulation of growth factor receptors associated with tyrosine kinases (Ray and Sturgill, 1987). Accumulating evidence suggests physiological and pathological roles for

The role of C5a in caspase activation: a novel molecular target for C5a

Cell death in development or disease is either programmed or accidental (Manjo and Joris, 1995). Programmed cell death or apoptosis is essential to the regulation of homeostasis in developing as well as adult multicellular organisms, but is often inappropriately triggered in models of neurodegeneration and neurodegenerative diseases such as AD (Lipton and Rosenberg, 1994; Cotman and Anderson, 1995; Kim et al., 1997; Michaelis et al., 1998; Yang et al., 1998). Recent work with the nematode

Conclusion

The importance of the complement system in AD neuropathology has been strongly indicated by a number of studies (Reviewed in Pasinetti, 1996). In particular, demonstration of the membrane attack complex along neuronal membranes suggests that complement activation contributes to neuronal lysis in AD (Webster et al., 1997). Also, studies showing the interaction of C1q with Aβ point to complement-mediated augmentation of Aβ neurotoxicity. On the other hand, complement proteins may also serve

Acknowledgements

This work was supported by grants from the National Institute of Aging: AG13799, AG14239, AG14766 to GMP.

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