. Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease. J Immunol. 2009 Jul 15;183(2):1375-83. PubMed.

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  1. In this study the researchers examined the role of the complement system in murine models of Alzheimer disease (AD). In human AD brains immunohistochemical studies have demonstrated that both early and late complement factors are found in amyloid plaques. Immunohistochemical studies in transgenic mice models for AD have shown the presence of the early complement factors in amyloid plaques also, but there is a lack of information about the presence of late complement factors (C5-C9) in such plaques (see Schwab et al., 2004). The present paper describes the effect of C5aT antagonists and the finding suggests indirectly the involvement of C5 in pathology. However, no direct information about an increase of C5 is given and also no immunohistochemical data demonstrating the presence of C5 in the amyloid plaques in the mouse.

    But despite these points, the paper is potentially very interesting. It seems that the role of the early complement factors (c1q, C3) is especially important in the aggregation, deposition, and removal of Aβ. Studies from Wyss-Coray, Tenner and Lemere in transgenic murine AD models point also in this direction. So, studying these early complement factors could be beneficial and helpful. C5a is a powerfull inflammatory mediator and could play a most important role in the organisation of the inflammation that could be toxic for neurons. It is, in this respect, highly interesting that the treatment with C5aR antagonist enhances behavorial performance. As written in this Alzforum news, the story is, at the moment, confusing. One of the possibities that emerges from the present paper from Fonseca et al., 2009 and that is in line with the earlier papers in transgenic mice, is that the early complement factors could be helpful in the removal of Aβ. If indeed C5a is the most powerful pro-inflammatory peptide of the complement cascade system for inducing an inflammatory response, then we can have an unraveling of the beneficial (early complement factors in Aβ removal) and the detrimental aspects of complement activation in AD (C5a as the toxic neuroinflammatory component).

    In summary, the present paper implies that we should pay more attention to the possible role of the late complement factors (from C5-C9) and to studies that demonstrate the presence and involvement of the late complement factors in animal AD models.

    References:

    . Transgenic mice overexpressing amyloid beta protein are an incomplete model of Alzheimer disease. Exp Neurol. 2004 Jul;188(1):52-64. PubMed.

    . Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease. J Immunol. 2009 Jul 15;183(2):1375-83. PubMed.