. 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. Epub 2009 Jun 26 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.


    . 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. Epub 2009 Jun 26 PubMed.

  2. The findings of Massaad and colleagues will advance our basic understanding of the neuroprotective role of mitochondrially targeted antioxidants in Alzheimer disease (AD) pathogenesis. Their findings suggest that mitochondrial superoxide dismutase 2 (SOD2) decreases hippocampal superoxide radicals, ameliorates learning/memory deficits, and decreases amyloid-β (Aβ) plaques in double transgenic mice that overexpress SOD2 and mutant human amyloid precursor protein. Interestingly, they also found a decreased ratio of Aβ1-42 to 1-40 in double transgenic mice. These findings further support the mitochondrial oxidative damage hypothesis of AD, and may have important implications for mitochondrially targeted antioxidant therapeutics in AD.

    Increasing evidence suggests that mitochondrial abnormalities are involved in the development and progression of AD (reviewed in Reddy, 2009). Further, it has been proposed that mitochondrially generated free radicals and oxidative damage are involved in abnormal processing of APP and in generating Aβ peptide by activating β- and γ-secretases (Reddy, 2006; Reddy and Beal, 2008). There is some evidence to support this hypothesis (Tamagno et al., 2008; Jin et al., 2008). Further, recently several groups (Crouch et al., 2005; Caspersen et al., 2005; Manczak et al., 2006; Devi et al., 2006; Hanson Petersen et al., 2008) found that Aβ peptide is localized to mitochondrial membranes and the mitochondrial matrix, and that mitochondrially localized Aβ peptide interacts with mitochondrial proteins, induces free radical production, decreases cytochrome oxidase activity, inhibits ATP production, and damages AD neurons. In addition, recent structural studies revealed that Aβ fragments mitochondria, suggesting that mitochondrial structural abnormalities (caused by Aβ) may be critical for mitochondrial dysfunction in AD (Wang et al., 2009; Mao et al., 2009). Overall, these studies suggest that Aβ and mitochondrial dysfunction play a big role in AD pathogenesis.

    To determine the role of overexpressed SOD2 in AD pathogenesis, Massaad et al. crossed SOD2 transgenic mice with Tg2576 mice and studied cognitive deficits, Aβ1-42 and 1-40 levels, and Aβ deposits in Tg2576 mice and double mutant mice (SOD2xTg2576 mice). They found decreased Aβ deposits and reduced cognitive deficits in double transgenic mice relative to Tg2576 mice, suggesting that mitochondrial superoxide dismutase improves cognitive functions in AD. However, it is still unclear 1) how overexpressed mitochondrial superoxide dismutase alters the ratio of Aβ1-42 to 1-40; and 2) how overexpressed mitochondrial superoxide dismutase improves learning and memory functions in double mutant mice. Further research is needed to find answers to these questions, and the answers may have some important implications to AD patients.

    Overall, findings of the study by Massaad and colleagues, together with previous studies (Hirai et al., 2001; Swerdlow et al., 1997; Reddy et al., 2004; Manczak et al., 2004; Caspersen et al., 2005; Manczak et al., 2006; Devi et al., 2006; Hansson Petersen et al., 2008; Wang et al., 2009), improve our understanding of mitochondrial oxidative damage in AD pathogenesis. Given the limited success of recent clinical trials using natural antioxidants in AD patients, findings from this new study may have some important implications for the development of mitochondrially targeted therapeutics for AD patients.

    See also:

    Mao P, Manczak M, Shree D and Reddy PH. Abnormal mitochondrial structural and functional changes caused by amyloid beta in Alzheimer’s disease. Paper presented at the International Conference on Alzheimer’s disease held Vienna, Austria July 11-16, 2009.


    . Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease. FASEB J. 2005 Dec;19(14):2040-1. PubMed.

    . Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction. J Neurosci. 2006 Aug 30;26(35):9057-68. PubMed.

    . The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13145-50. PubMed.

    . Mitochondrial abnormalities in Alzheimer's disease. J Neurosci. 2001 May 1;21(9):3017-23. PubMed.

    . DNA damage-inducing agents elicit gamma-secretase activation mediated by oxidative stress. Cell Death Differ. 2008 Sep;15(9):1375-84. PubMed.

    . Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet. 2006 May 1;15(9):1437-49. PubMed.

    . Differential expression of oxidative phosphorylation genes in patients with Alzheimer's disease: implications for early mitochondrial dysfunction and oxidative damage. Neuromolecular Med. 2004;5(2):147-62. PubMed.

    . Amyloid precursor protein-mediated free radicals and oxidative damage: implications for the development and progression of Alzheimer's disease. J Neurochem. 2006 Jan;96(1):1-13. PubMed.

    . Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer's disease. Exp Neurol. 2009 Aug;218(2):286-92. PubMed.

    . Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol Med. 2008 Feb;14(2):45-53. PubMed.

    . Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease. Hum Mol Genet. 2004 Jun 15;13(12):1225-40. PubMed.

    . Cybrids in Alzheimer's disease: a cellular model of the disease?. Neurology. 1997 Oct;49(4):918-25. PubMed.

    . Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor protein. J Neurochem. 2008 Feb;104(3):683-95. PubMed.

    . Impaired balance of mitochondrial fission and fusion in Alzheimer's disease. J Neurosci. 2009 Jul 15;29(28):9090-103. PubMed.

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