. Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J Neurosci. 2008 Jun 18;28(25):6333-41. PubMed.

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  1. This important study by Cynthia Lemere of Brigham and Women’s Hospital and collaborators at Harvard Medical School further supports a beneficial role of intracerebral activation of the complement system, possibly by promoting phagocytosis of Aβ. First authors Marcel Maier and Ying Peng, and colleagues have generated a C3-deficient amyloid precursor protein (APP) transgenic mouse model of Alzheimer’s disease (AD) to specifically investigate the role of the complement system central component C3. APP transgenic mice lacking C3 were found to exhibit increased amyloid plaque burden, enhanced neurodegeneration, and shifted microglia activation toward a phenotype often found to be associated with tissue repair processes. These observations further support a beneficial role for complement component C3 in plaque clearance in APP mice. This is in line with a previous report describing enhanced pathology in APP transgenic mice with brain-targeted expression of a soluble form of complement receptor-related protein y (sCrry), a potent inhibitor of C3 convertases (Wyss-Coray et al., 2002).

    Brain cells can produce and mount a fully functional complement system. Together with a wealth of histopathological reports describing the presence of complement proteins in senile amyloid plaques and neurofibrillary tangles, intracerebral activation of the complement system has long been associated with inflammatory processes thought to drive AD pathology. Furthermore, neurons, because they express low levels of complement regulators, have the propensity to spontaneously activate the complement system in vitro in an antibody-independent manner. As a consequence, neurons are believed to be especially susceptible to complement-mediated lysis (Singhrao et al., 2000).

    Overall, the ability of the complement system to serve as a defense system has probably been overlooked. This view is now emerging and this paper by Marcel Maier, Ying Peng, and collaborators further supports the hypothesis that the complement system may actively participate in helping clear the plaques. However, given the complexity of the complement system, it is expected that different arms of the complement cascade are involved in different - beneficial or harmful – processes. Several examples can illustrate this view: 1) APP transgenic mice lacking C1q, the first component of the classical cascade, exhibit less neuropathology, suggesting a detrimental effect of C1q on neuronal integrity (Fonseca et al., 2004). Interestingly, increased activation of the alternative pathway in these mice may also contribute to the observed decreased pathology; 2) As mentioned above and pointed out by Pat McGeer in his comments to the paper by Lemere and colleagues, intracerebral activation of the terminal lytic membrane attack complex is likely to lead to severe damaging effect; and 3) On the other hand, proinflammatory anaphylatoxins C3a and C5a, generated upon complement activation, have previously been reported to be neuroprotective in vitro (van Beek et al., 2003). Overall, the lack of brain-penetrant pharmacological tools to dampen the complement system at different level of activation is a clear limitation to the further understanding of the complex involvement of complement in experimental disease models.

    Data with APP transgenic mice have been overall very informative. However, as suggested by Pat McGeer, these models are incomplete models of AD, partly because APP transgenic mice display weaker inflammation and complement activation than what is observed in AD patients. In light of this, it is difficult to predict how the observations by Marcel Maier, Ying Peng, and colleagues will translate in AD patients. We cannot rule out the possibility that the balance required in experimental models of AD for the complement system to promote plaque clearance may be shifted in AD patients.

    Targeting Aβ by active or passive immunization have consistently been reported to be effective in APP-overexpressing mouse models. Translation in humans proved problematic when AN1792 immunotherapy vaccine trial initiated by Elan Pharmaceuticals was halted because approximately 6% of the volunteers developed encephalitis. Although interrupted, this trial indicated that Aβ immunotherapy still holds promises for the treatment of AD. Long-term follow up of patients immunized with AN1792 has unveiled reduced functional decline in antibody responders. Additionally, postmortem histological analysis of brains of AD patients that had been immunized with AN1792 is suggestive of patchy plaque clearance from affected brain tissue.

    The exact mechanisms by which either active or passive immunization approaches may promote plaque clearance are still unknown. The study by Lemere and collaborators certainly paves the way to a better understanding of mechanisms underlying the brain’s ability to recognize plaques, initiate defense mechanisms, and promote plaque clearance. Further experimental work along that line that will help design better and safer strategies to treat AD is warranted.

    References:

    . Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer's disease. J Neurosci. 2004 Jul 21;24(29):6457-65. PubMed.

    . Spontaneous classical pathway activation and deficiency of membrane regulators render human neurons susceptible to complement lysis. Am J Pathol. 2000 Sep;157(3):905-18. PubMed.

    . Activation of complement in the central nervous system: roles in neurodegeneration and neuroprotection. Ann N Y Acad Sci. 2003 May;992:56-71. PubMed.

    . Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10837-42. PubMed.

    . Complement C3 and C4 expression in C1q sufficient and deficient mouse models of Alzheimer's disease. J Neurochem. 2008 Sep;106(5):2080-92. PubMed.

  2. The complexity of the role of complement in Alzheimer disease has been further reinforced by this publication from Lemere and colleagues reporting increased Aβ deposition in 17-month APP C3-/- relative to the APP (J20) C3 sufficient mice. As noted by others in this forum, the use of complement-deficient and transgenic rodent models has provided support for both detrimental (Fonseca et al., 2004) and beneficial (Maier et al., 2008; Wyss-Coray et al., 2002) roles of specific complement components in AD models. Certainly the increased expression of complement components and its activation products shown by many labs provide evidence that it is present and activated in mouse models and in the human disease. Others have also seen reduction in pathology using complement inhibitors in APP mouse models (Bergamaschini et al., 2004) and more studies should be forthcoming soon.

    In the APPC3-/- animal model reported here by Maier and colleagues, an increase in plaque load, neuronal loss (albeit quite small), and CD45 staining in the plaque area in the APPC3-/- animals relative to the C3 sufficient APP transgenics were observed. This contrasts with a twofold increase in neuronal markers MAP2 and synaptophysin (i.e., neuronal integrity) and a significant decrease in microglial markers (MAC1, F4/80, and IA/IE) in the absence of C1q in the Tg2576 model. In a recently published manuscript, mentioned by van Beek above, we demonstrate that C3 is deposited on the thioflavine-positive plaques in the Tg2576C1q-/- (Zhou et al., 2008) presumably via direct deposition of C3 (i.e., alternative complement pathway activation). This supports the hypothesis that complement components can mediate protective events as well as detrimental events in this disease. At this time the reason for the difference in outcome due to classical or alternative pathway activation is unknown, since kinetics or absolute level of activation cannot be determined by the immunohistochemical analysis performed. Protective effects have also been reported for C1q (Pisalyaput and Tenner, 2008), C3a (Rahpeymai et al., 2006), and C5a (Osaka et al., 1999), although again at this time, the mechanisms underlying each of these scenarios is not yet understood.

    However, it is critical to keep in mind that each model of AD/amyloidosis/tauopathy is on different strains, and subtle differences over the lifetime of the animal may account for some/many of the differences. In addition, compensatory or redundant pathways may develop over the lifetime of any knockout mouse. Furthermore, effects may differ between the early and late stages of the disease (which develop at different ages in the different models).

    As Lemere and colleagues note, the increased pathology in the APPC3-/- animals was seen at the “advanced” age of 17 months for the J20 (APP) mouse, and well beyond the appearance of potentially complement-activating thioflavine-positive plaques, as the 12-month data demonstrate. Thus, the lack of differences in the 12-month animals with and without C3 is also puzzling, and does not seem to support the hypothesis proposed based on the C1q-/- model that C5a (or C3a) plays a significant, if partial, role in recruitment of glia to the plaques (Fonseca et al., 2004). As others have pointed out, it is interesting that the C3-/- APP animals had a cytokine profile characteristic of M2 macrophages, i.e., elevated IL-4 and IL-10. Whether this is due to anti-inflammatory signaling of C1q on plaques in the absence of C5a signaling in the C3-/- APP mice and/or a persistent lack of clearance of Aβ in the absence of opsonizing C3b, or to a predisposition to M2 due to the complete lack of C3 during the lifetime of the animal, remains to be determined.

    Nevertheless, each model provides opportunities for assessing the multiplicity of factors that may influence the pathology and loss of cognitive ability in the human disease. There is a complexity and variety of functions of the complement components (and their inhibitors and cell receptors), and a clear importance of achieving balanced responses in order to permit neuroprotection (and repair?) but prevent neurodegeneration. All this necessitates a thorough understanding of the activities mediated by these components and their activation products. In the end, the optimal treatment for AD may very well consist of a therapy combining targeting of complement components and/or inflammation, amyloid production and/or deposition, and neuroprotective strategies.

    References:

    . Peripheral treatment with enoxaparin, a low molecular weight heparin, reduces plaques and beta-amyloid accumulation in a mouse model of Alzheimer's disease. J Neurosci. 2004 Apr 28;24(17):4181-6. PubMed.

    . Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer's disease. J Neurosci. 2004 Jul 21;24(29):6457-65. PubMed.

    . Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J Neurosci. 2008 Jun 18;28(25):6333-41. PubMed.

    . Complement-derived anaphylatoxin C5a protects against glutamate-mediated neurotoxicity. J Cell Biochem. 1999 Jun 1;73(3):303-11. PubMed.

    . Complement component C1q inhibits beta-amyloid- and serum amyloid P-induced neurotoxicity via caspase- and calpain-independent mechanisms. J Neurochem. 2008 Feb;104(3):696-707. PubMed.

    . Complement: a novel factor in basal and ischemia-induced neurogenesis. EMBO J. 2006 Mar 22;25(6):1364-74. PubMed.

    . Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10837-42. PubMed.

    . Complement C3 and C4 expression in C1q sufficient and deficient mouse models of Alzheimer's disease. J Neurochem. 2008 Sep;106(5):2080-92. PubMed.