Complement C3 Deficiency Leads to Accelerated Amyloid Plaque Deposition and Neurodegeneration and Modulation of the Microglia/Macrophage Phenotype in Amyloid Precursor Protein Transgenic Mice

Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2008; 28(25):6333-41. DOI: 10.1523/JNEUROSCI.0829-08.2008
Source: PubMed


Complement factor C3 is the central component of the complement system and a key inflammatory protein activated in Alzheimer's disease (AD). Previous studies demonstrated that inhibition of C3 by overexpression of soluble complement receptor-related protein y in an AD mouse model led to reduced microgliosis, increased amyloid beta (Abeta) plaque burden, and neurodegeneration. To further address the role of C3 in AD pathology, we generated a complement C3-deficient amyloid precursor protein (APP) transgenic AD mouse model (APP;C3(-/-)). Brains were analyzed at 8, 12, and 17 months of age by immunohistochemical and biochemical methods and compared with age-matched APP transgenic mice. At younger ages (8-12 months), no significant neuropathological differences were observed between the two transgenic lines. In contrast, at 17 months of age, APP;C3(-/-) mice showed significant changes of up to twofold increased total Abeta and fibrillar amyloid plaque burden in midfrontal cortex and hippocampus, which correlated with (1) significantly increased Tris-buffered saline (TBS)-insoluble Abeta(42) levels and reduced TBS-soluble Abeta(42) and Abeta(40) levels in brain homogenates, (2) a trend for increased Abeta levels in the plasma, (3) a significant loss of neuronal-specific nuclear protein-positive neurons in the hippocampus, and (4) differential activation of microglia toward a more alternative phenotype (e.g., significantly increased CD45-positive microglia, increased brain levels of interleukins 4 and 10, and reduced levels of CD68, F4/80, inducible nitric oxide synthase, and tumor necrosis factor). Our results suggest a beneficial role for complement C3 in plaque clearance and neuronal health as well as in modulation of the microglia phenotype.

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Available from: Timothy J Seabrook
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    • "Other studies using pharmacologic and genetic means to suppress innate immune activation in similar mouse models have revealed conflicting results . Some manipulations designed to suppress innate immune activation appear to decrease Ab accumulation and improve ADassociated phenotypes in these models, whereas others have deleterious effects and promote Ab accumulation and worsen AD phenotypes (Chakrabarty et al., 2012; El Khoury et al., 2007; Kiyota et al., 2010; Maier et al., 2008; Richard et al., 2008; Vom Berg et al., 2012). Furthermore, clinical trials with anti-inflammatory agents have failed to clearly show any evidence of beneficial effect in AD patients (Breitner et al., 2011; Leoutsakos et al., 2012). "
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    • "), yet this data remains controversial (Wyss-Coray et al., 2002; Loeffler, 2004; Maier et al., 2008). Nevertheless, our data support the view that targeting the complement system and other inflammatory pathways poses an intriguing possibility for the treatment of agingassociated diseases and cognitive decline, which has recently been demonstrated for inhibition of NF-κB signaling in a mouse model of AD (Liu et al., 2014). "
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    • "One potential neuroprotective activity of CS is indicated by the results of experiments performed on C3-deficient (C3−/−) animals. Maier et al. found that complete C3 deficiency leads to accelerated amyloid í µí»½ plaque deposition with animal aging and thus augments neurodegeneration [90]. The authors conclude that the presence of C3 is potentially necessary for anti-inflammatory cytokine-mediated stimulated microglial phagocytosis of amyloid and other cellular debris. "
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