A variety of inflammatory processes is increased in regions of pathology in the Alzheimer's disease (AD) brain.
There is a reciprocal relationship between this local inflammation and senile plaques (SPs) and neurofibrillary tangles (NFTs); both SPs and NFTs, as well as damaged neurons and neurites, stimulate inflammatory responses, and inflammatory processes exert multiple effects, some of which promote neuropathology.
Numerous retrospective studies have shown that long-term administration of nonsteroidal anti-inflammatory drugs (NSAIDs) to individuals with arthritis significantly reduces the risk for these individuals for developing AD.
These findings, together with the demonstration of elevated glial cell activation, complement activation, and increased acute phase reactant production at sites of pathology in the AD brain, support the hypothesis that local inflammation may contribute to the development of this disorder.
Although a short-term trial of AD patients with the NSAID indomethacin suggested protection from cognitive decline, subsequent trials with other anti-inflammatory drugs have found no evidence for slowing of the dementing process.
These findings underscore the current perception of CNS inflammation as a "double edged sword", with neuroprotective roles for some inflammatory components and neurotoxic effects for others.
The significance of complement activation, a major inflammatory mechanism, in AD is particularly problematic.
The complement system is composed of more than 30 plasma and membrane-associated proteins which function as an inflammatory cascade.
Complement activation promotes the removal of microorganisms and the processing of immune complexes.
The liver is the main source of these proteins in peripheral blood, but they are also synthesized in other organs including the brain.
Protein fragments generated during activation of the system enzymatically cleave the next protein in the sequence, generating a variety of "activation proteins" with diverse activities (Table 1).
Table 1. Biological activities of complement activation proteins, with relevance to AD.
||Enhances Aβ (amyloid beta) aggregation; may facilitate Aβ clearance; enhances Aβ-induced cytokine secretion by microglia
||Anaphylatoxin (increases capillary permeability); protects neurons vs. excitotoxicity
||Immune adherence and opsonization (may facilitate Aβ clearance by phagocytic microglia)
||Anaphylatoxin; protects neurons vs. excitotoxicity; chemotaxic attraction of microglia; inhibits apoptosis; increases cytokine release from Aβ-primed monocytes
||Neurotoxicity; sublytic concentrations may have both pro- and anti- inflammatory activities
Three complement pathways, the classical, alternative, and lectin-mediated cascades, have been identified (Figure 1).
Full activation results in the generation of C5b-9, the "membrane attack complex" (MAC), which penetrates the surface membrane of susceptible cells, on which it is deposited, and may result in cell death if present in sufficient concentration.
The presence of early complement activation proteins and of the MAC has been demonstrated by immunocytochemical staining in the AD brain.
Subsequent studies found that complement activation increases Aβ aggregation and potentiates its neurotoxicity, attracts microglia, promotes microglial and macrophage secretion of inflammatory cytokines, and induces neuronal injury, and, sometimes, neuronal death, via the MAC.
These findings suggested that complement activation might contribute to the neurodegenerative process in AD.
However, recent studies have also revealed neuroprotective functions for some complement activation proteins, including in vitro protection against excitotoxicity and Aβ-induced neurotoxicity, as well as anti-apoptotic apoptotic effects.
Schematic diagram of classical, alternative, and lectin complement activation pathways.
There is evidence for activation of the classical and alternative pathways in the AD brain.
Further, C1q, the first complement protein to be deposited on cell membranes during activation of the classical complement sequence, may facilitate the clearance of Aβ by microglia, although this is controversial.
Understanding the role of complement activation in AD is of clinical relevance because some complement-inhibiting drugs are available, and others are being developed.
Conditions for which these agents are currently being investigated include stroke, organ transplantation, glomerulonephritis, ischemic cardiomyopathy, and hereditary angioedema.
Modulation of CNS complement activation in experimental animal models of AD, both by treatment with complement-inhibiting drugs and by generation of AD-type pathology in complement-deficient animals, should be useful for obtaining a greater understanding of the role of this process in the development of AD-type pathology.
Unfortunately, knowledge of the extent of complement activation in animal models is lacking.
While animal models of human disease generally have similar pathological findings to the human disorders, distinct differences remain.
These models may be appropriate for studying some aspects of a disease process, while less suitable for others.
To determine the significance of complement activation in the development of AD-type pathology, for example, some animal models may be of value primarily for investigating the relationship between early complement activation and SP and NFT formation, whereas others may be more relevant for studying the role of the MAC in neuronal loss.
Complement activation has been extensively studied in the AD brain.
There is convincing evidence for activation of both the classical and alternative pathways, resulting in full activation as indicated by the presence of the MAC.
Both aggregated Aβ (in SPs) and phosphorylated tau (in NFTs) are likely to be responsible for this activation.
Because complement activation generates both neuroprotective and neurotoxic effects, the significance of increased complement activation in the development and progression of AD is unclear.
An optimal animal model for studying the significance of complement activation in the development of AD-type pathology would have complete activation of this process, with co-localization of complement activation proteins with SPs and with NFTs (if present).
Other desirable features include early complement activation prior to the development of extensive neuropathology, increased CNS production of native complement proteins, and both classical and alternative pathway activation.
Surprisingly little is known about the extent of complement activation in animal models of AD.
The postischemic hyperthermic rat is the only animal model of AD in which full complement activation has been reported.
The few studies with APP-transgenic mice have yielded conflicting results, with one investigation suggesting a neuroprotective role for complement activation, while another found that early complement activation (as indicated by C1q deposition) was associated with a loss of neuronal integrity.
Transgenic mouse models may be problematic for studies of AD-related complement activation because of inherent deficiencies in mouse complement activation and inefficient activation of mouse complement by the human Aβ present in the SPs in these animals.
Other animal models in which SPs (and NFTs, if present) are of endogenous, rather than human, origin offer alternatives to transgenic mice for studying this issue.
The extent of complement activation and its association with neuropathology must be determined in animal models of AD to clarify the relevance of these models for investigating the significance of complement activation in the development of AD-type pathology.