. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet. 2006 Sep;38(9):1055-9. PubMed.

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  1. Complement is activated in most forms of neurodegeneration and in AD in particular. Aβ aggregates (the particular conformation of which is ill-defined) can activate complement and may trigger the clearance of Aβ in solution via C3bi and complement receptors (Mac1/CR3) on microglia. Similarly, tangle ghosts may be a trigger for complement activation.

    It has also been suggested that injured cells or possibly Aβ aggregates bound to cell surfaces lead to activation of complement. This cell-bound activation of complement could lead to formation of the membrane attack complex (MAC) and further damage of cells, although studies in oligodendrocytes show that the MAC, which is a membrane pore, can also induce protective pathways in cells.

    Factor H is involved in the regulation of the alternative complement pathway and may influence any of the above activities. If Factor H does indeed have a role in the degeneration of cells in the eye, it may have a similar role in the hippocampus and cortex as well. At this point, however, there is little hard evidence from in-vivo studies to support a role for complement in neurodegeneration, and more studies need to be done.

    View all comments by Tony Wyss-Coray
  2. The Complement System and Age-related Macular Degeneration: What Does It Teach Us about Alzheimer Disease?
    Age-related macular degeneration (AMD) and Alzheimer disease (AD) are both neurodegenerative diseases of aging, with loss of photoreceptors and CNS neurons, respectively. A number of recent studies have shown that polymorphisms of several complement proteins in the alternative pathway of complement activation (CFB, C2, and CFH) enhance susceptibility to AMD. Somewhat similarly, in AD there is a profound increase in the levels of the initiating protein of the complement cascade called C1q, a prominent upregulation of which has also recently been reported to accompany glaucoma, which is a neurodegenerative retinal disease of aging. All of these changes, in AMD and AD, ultimately lead to activation of the pivotal complement protein called C3. Upon activation, C3 is fragmented into several pieces. One is called C3a, a small cytokine-like molecule that activates microglia and stimulates angiogenesis, whereas a larger fragment, called C3b, opsonizes the cell or debris where it was generated, leading to phagocytosis (or sometimes cell lysis).

    What does the association of complement pathway malfunction in AMD have to teach us about neurodegeneration in AD? First, complement activation has recently been linked to the strong stimulation of angiogenesis that contributes to the pathophysiology of AMD. When C3 activation is prevented in AMD, neovascularization is inhibited (Nozaki et al., 2006; Bora et al., 2005; Girardi et al., 2006). Is it possible that complement activation in AD could lead to abnormal angiogenesis that could contribute to AD pathophysiology? There is little data as of yet, but the possibility has been suggested previously (for instance, Zlokovic, 2005; Vagnucci and Li, 2003) and an increase in microvascularization in AD brain was reported previously by Perlmutter et al. (1990). Interestingly β amyloid peptide injected into a normal rat hippocampus has been found to stimulate angiogenesis (Zand et al., 2005) and fibrillar β amyloid is a well-known activator of C1q and thus the classical complement cascade.

    Second, complement activation leads to a dramatic activation of microglia, both in the retina and throughout the CNS. Microglia are a crucial source of many components of the complement cascade and other factors that may enhance inflammation. Amyloid-β also enhances microglial activation, and has been reported to be deposited at sites of complement activation in Drusen deposits in AMD (Johnson et al., 2002). In fact, amyloid-β triggers retinal pigment epithelial cells (a class of phagocytic cells within the retina implicated in retinal photoreceptor degeneration) to release VEGF and other factors that promote angiogenesis (Yoshida et al., 2005). Microglia have recently been shown to play a role in developmental blood vessel formation in the retina (Checchin et al., 2006), which is of interest given their close association with blood vessels and their activation in neurodegenerative diseases in general.

    Breakdown of the blood-brain barrier (and blood-retinal barrier) has been increasingly observed and invoked in AMD and AD. Newly formed vessels are leaky, as are microvessels involved in angiopathy observed in both AMD and AD. This may be crucially important in driving the pathology forward, as the blood is the major source of all complement proteins. Activated microglial cells and many neurons and glial cells also make certain complement components. If capillaries become leaky, key complement proteins such as C3 may leak in (and complement activation itself may in turn further enhance the leakiness of these vessels). C3 is the key complement protein that mediates complement activation in all pathways of complement activation. Its endogenous sources within the normal and injured brain are still quite mysterious. There is evidence that activated microglial cells and peripheral macrophages clearly make it; possibly other cell types can make it, as well. The brain cell type identities that produce each complement component are important questions for future work.

    The above observations suggest that age-related neurodegenerative diseases such as AMD and AD may share in common underlying mechanisms, particularly the activation of the complement pathways, leading to C3 activation, microglial activation, vascular changes and angiogenesis, amyloid production, and neuroinflammatory tissue damage. Sorting out the relative importance and sequence of these events is an important task for the future. But the linkage of AMD susceptibility to complement pathway polymorphisms clearly shows the important contribution of complement proteins in AMD to disease initiation and/or progression, and the high levels of C1q protein in AD brains suggest an important role for complement proteins in AD, as well.

    An important unanswered question is how complement pathway activation begins in AMD and AD. A primary way that the complement cascade becomes initiated is by the presence of abnormal cell surfaces which become opsonized by short pentraxins such as C-reactive protein or antibodies that in turn can both bind to C1q. In AMD, it is entirely unclear how the alternative pathway would become activated, as microbial surfaces are not implicated. The potential role of the classical complement cascade in AMD should now be examined. CFH not only controls activity of the alternative complement pathway but of the other complement pathways, as well, as its function is to inactivate the C3 complement protein that is central to all complement paths of activation. A still relatively underexplored question is the extent to which degenerating tissues become immunogenic. We have recently found that degenerating myelin in the peripheral nervous system is strongly immunogenic and that autoantibodies are generated to degenerating myelin that are actually necessary for its clearance (Vargas and Barres, SFN abstract, 2005 and submitted). Similarly it is possible that autoantibodies are generated against degenerating retinal tissue in AMD or brain tissue in AD. As cell surface antigens in retinal and brain cryosections are only poorly accessible to antibodies in immunostaining methods, it has been difficult to address this question experimentally. A great way forward, where relevant animal models for neurodegenerative disease are available, will be to examine the effects on the neurodegenerative process when these animals are crossed to antibody-deficient strains of mice such as the JhD mutant mouse that entirely lacks B cells.

    Lastly, the central importance of complement proteins in determining AMD susceptibility raises an important question. Could the exponential increase in age-dependent susceptibility to neurodegenerative disease be caused by an age-related change in the complement system? Possibly complement protein levels might increase with age, or important complement inhibitors might decrease with age. While the identification of polymorphisms in genes encoding complement proteins is an important step toward understanding AMD and further supports the potential long-suggested relevance of complement proteins in AD, it also raises many new questions for future studies.

    View all comments by Ben Barres
  3. The complement system plays important roles not only in the neurodegeneration seen in AD and AMD, but also during normal brain aging. We reported that the activation of the early components of the complement appears to target myelin and oligodendrocytes in the aged rhesus monkey brain. Interestingly, the complement activation was also observed in the young brain, but to a much lesser extent. These findings suggest that only an exaggerated complement activation is detrimental, but that low-level activation may be physiologic and could be crucial for the turnover of myelin (Duce et al., 2006.)

    View all comments by Carmela Abraham
  4. There is considerable data suggesting that complement plays a role in the progression of AD, including an animal model that we published in 2004. In that study, Tg2576 animals (APP) were crossed with C1q-deficient mice to effectively eliminate activation of the classical pathway of complement. The pathology of APPQ-/- was compared with that of APP mice and B6SJL controls at 3-16 months of age by immunohistochemistry and Western blot analysis. While at younger ages (3-6 months) when no plaque pathology was present, no significant differences were seen; at older ages (12 and 16 months), the level of activated glia surrounding the plaques was significantly lower in the APPQ-/- mice. In addition, although Tg2576 mice showed a progressive decrease in synaptophysin and MAP2 in the CA3 area of hippocampus compared with control B6SJL at 9, 12, and 16 months, the APPQ-/- mice had significantly less of a decrease in these markers at 12 and 16 months. Interestingly, the APP and APPQ-/- mice developed comparable total amyloid and fibrillar β amyloid in frontal cortex and hippocampus.

    The data are consistent with a deleterious role for complement at ages when the fibrillar plaques (that have been shown to activate complement in vitro, and to be selectively associated with complement components in human AD brain) are present, most likely through the activation of the classical complement cascade and the enhancement of inflammation. There are observations that imply that complement can also have a protective effect in the brain. There are indeed multiple points within the complement cascade in which protective effects can be exerted. Some of these were discussed in recent reviews, but others are likely to be uncovered as the use of additional animal models and modulators of complement activity are tested.

    View all comments by Andrea Tenner
  5. Besides providing further evidence that the complement cascade is involved in neurodegeneration, these articles have broader implications for the field of genetics and disease mapping. Through a combination of linkage mapping (1-5) and association studies (6-8), the original reports declared that a tyrosine-to-histidine substitution at position 402 accounted for 20-50 percent of the overall risk of developing age-related macular degeneration (AMD). However, in the current reports, the coding change does not appear to have the largest effect. This has two implications for the field of neurogenetics. First, that it should not be assumed that examining single coding changes in genes is sufficient. With the recent boom in whole genome studies, this should no longer be as much of a problem for the field. But it does suggest that perhaps a re-examination of current association results is in order. Alzgene reports that after meta-analysis of 341 genes, 20 variants in 13 genes are significant. Approximately one-third of those are coding changes; however, in light of the recent findings with AMD, perhaps rather than trying to further replicate these specific polymorphisms, whole genes should be analyzed using HapMap data. Second, these studies also imply that for common diseases, it is genes and their alleles that matter, not individual polymorphisms. This is one of the reasons haplotype analysis can be more powerful than examining single SNPs. Within the first reports, the coding polymorphism divided the population into risk and non-risk; however, the current reports now identify multiple risk and protective CFH alleles. Thus, within the population, it is the collection of SNPs, not any single change, which creates risk (or in this case, protection). This seems obvious, but it was impossible to efficiently examine the genetic content of genes as a whole until recently. Again, with the advent of full genome scans, there is now the possibility to capture complete information about the genome and perform more quantitative analysis of phenotypes rather than just treating all individuals as risk and non-risk.

    View all comments by Amanda Myers

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  1. Sharp Look at Complement in Genetics of Macular Degeneration