Yin and Yang: complement activation and regulation in Alzheimer’s disease
Introduction
Historically, the brain has been considered an immunologically privileged organ. This perceived privilege was based in part upon the presence of the blood–brain barrier (BBB), which prevents the entry of blood-born cells, proteins and other factors involved in regulating the peripheral immune system into the central nervous system (CNS). However, mounting evidence indicates that this privilege is not absolute, and that various immune and inflammatory mechanisms operate actively within the brain, particularly in response to disease or injury, and may play a role in the pathogenetic processes (Eikelenboom and Stam, 1982, Haga et al., 1993, Griffin et al., 1995, McGeer et al., 1989, Rogers et al., 1992, Shen et al., 1998, Shen et al., 2001, Yang et al., 2000). These findings have contributed to the rapidly evolving field of neuroimmunology and bring with it emerging opportunities to develop novel agents that may prevent or significantly retard the neurodegenerative processes underlying Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), AIDS dementia complex (ADC), amyotrophic lateral sclerosis (ALS) and stroke. This mini-review focuses only on the role of the complement system in Alzheimer’s disease since complement proteins constitute a large portion of inflammatory mediators in the human body.
Alzheimer’s disease is characterized by extracellular senile plaques, intracellular neurofibrillary tangles and neuronal loss (Price and Sisodia, 1998, Selkoe et al., 1996, Sisodia and Gallagher, 1998). The major component of senile plaques is amyloid-β-peptide (Aβ), a group of 39-43 amino acid peptides derived from the amyloid precursor protein (APP) (Glenner and Wong, 1984, Ashall and Goate, 1994, Masters et al., 1985, Price and Sisodia, 1998, Selkoe et al., 1996). The fact that Aβ is detected in both normal and AD brains (Ashall and Goate, 1994) indicates that Aβ alone may not be sufficient to cause AD. In recent years, the occurrence of inflammatory proteins in the AD brain have been widely reported (Afagh et al., 1996, Eikelenboom and Stam, 1982, Griffin et al., 1995, McGeer et al., 1991, Rogers et al., 1992, Shen et al., 1997, Shen et al., 2001, Veerhuis et al., 1998, Walker and McGeer, 1992, Webster et al., 1997, Yang et al., 2000). One prominent feature of AD neuropathology is the association of activated proteins of the classical complement pathway with the lesions (Eikelenboom and Stam, 1982, Zhan et al., 1994, McGeer et al., 1991, Rogers et al., 1992, Shen et al., 1997). The full range of classical pathway complement proteins from C1q to C5b-9 (membrane attack complex (MAC)) have been found highly localized with compacted or β-pleated Aβ deposits in neuritic plaques (McGeer et al., 1989, O’Barr et al., 2001, Rogers et al., 1992, Shen et al., 1997, Shen et al., 1998, Yang et al., 2000). The fact that complement activation has progressed until the MAC stage indicates that the regulatory mechanisms of the complement system have been unable to halt the complement activation process. Some complement regulators have been found in association with the AD lesions (McGeer et al., 1991, Singhrao et al., 2000, Walker et al., 1995, Yang et al., 2000). This is a further proof of complement activation in the lesions but also an indication that the regulators have been able to control complement activation only to a limited extent.
Clinical studies have also suggested a pathophysiological role for inflammation in AD (Breitner et al., 1994, McGeer et al., 1996, Rich et al., 1995, Rogers et al., 1993). From a therapeutic point of view, several direct studies on twins (Breitner et al., 1994) and a recent “ibuprofen” clinical trial (Rich et al., 1995) have provided evidence that nonsteroidal anti-inflammatory drug (NSAIDs) are one potential means of reducing inflammation in AD. Similar results were also obtained from a small double-blind, placebo-controlled trial using Indomethacin for AD prevention, a common NSAID (McGeer et al., 1996, Rogers et al., 1993). NSAIDs are not very effective direct inhibitors of complement (Wegger et al., 2001), but they can inhibit the inflammatory consequences of complement activation, particularly those that are mediated by mast cells and other leukocytes.
Section snippets
Roles of complement activation in Alzheimer’s disease
Activation of any of three complement pathways (classical, lectin or alternative pathway) in the human body is very important in normal inflammatory responses to injury and in removing invading microbes (Reid and Porter, 1981). It is also a very important clean-up system in removing apoptotic cells, tissue debris and macromolecular aggregates (Muller-Eberhard, 1988). However, complement activation can also cause cell injury or death when activated inappropriately. Thus, although complement
Utilization of animal models
It would be valuable and important to examine the complement inhibiting compounds or proteins using in vitro models for AD treatment. Since animal models for Aβ deposition and AD are now available, they can be used for in vivo testing. For example, if some of these complement inhibitors block Aβ-induced complement activation, would they then also inhibit microglial cell activation in both in vitro and in vivo models? Since some of the complement inhibitors are synthesized by neurons, what are
Acknowledgements
We thank K. Lindholm, G. Arnold, R. Lee and M. Guerilla for technical assistance during this manuscript preparation. This work was supported by grants from the Alzheimer’s Association, The Academy of Finland and The Sigrid Juselius Foundation.
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