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

ABSTRACT 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, Sep 28, 2015
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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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    ABSTRACT: Anti-inflammatory strategies are proposed to have beneficial effects in Alzheimer's disease. To explore how anti-inflammatory cytokine signaling affects Aβ pathology, we investigated the effects of adeno-associated virus (AAV2/1)-mediated expression of Interleukin (IL)-10 in the brains of APP transgenic mouse models. IL-10 expression resulted in increased Aβ accumulation and impaired memory in APP mice. A focused transcriptome analysis revealed changes consistent with enhanced IL-10 signaling and increased ApoE expression in IL-10-expressing APP mice. ApoE protein was selectively increased in the plaque-associated insoluble cellular fraction, likely because of direct interaction with aggregated Aβ in the IL-10-expressing APP mice. Ex vivo studies also show that IL-10 and ApoE can individually impair glial Aβ phagocytosis. Our observations that IL-10 has an unexpected negative effect on Aβ proteostasis and cognition in APP mouse models demonstrate the complex interplay between innate immunity and proteostasis in neurodegenerative diseases, an interaction we call immunoproteostasis. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 01/2015; 85(3). DOI:10.1016/j.neuron.2014.11.020 · 15.05 Impact Factor
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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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    ABSTRACT: Aging is accompanied by gradually increasing impairment of cognitive abilities and constitutes the main risk factor of neurodegenerative conditions like Alzheimer's disease (AD). The underlying mechanisms are however not well understood. Here we analyze the hippocampal transcriptome of young adult mice and two groups of mice at advanced age using RNA sequencing. This approach enabled us to test differential expression of coding and non-coding transcripts, as well as differential splicing and RNA editing. We report a specific age-associated gene expression signature that is associated with major genetic risk factors for late-onset AD (LOAD). This signature is dominated by neuroinflammatory processes, specifically activation of the complement system at the level of increased gene expression, while de-regulation of neuronal plasticity appears to be mediated by compromised RNA splicing.
    Frontiers in Cellular Neuroscience 11/2014; 8(373):1-15. DOI:10.3389/fncel.2014.00373 · 4.29 Impact Factor
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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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    ABSTRACT: Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly, especially in Western countries. Although the prevalence, risk factors, and clinical course of the disease are well described, its pathogenesis is not entirely elucidated. AMD is associated with a variety of biochemical abnormalities, including complement components deposition in the retinal pigment epithelium-Bruch's membrane-choriocapillaris complex. Although the complement system (CS) is increasingly recognized as mediating important roles in retinal biology, its particular role in AMD pathogenesis has not been precisely defined. Unrestricted activation of the CS following injury may directly damage retinal tissue and recruit immune cells to the vicinity of active complement cascades, therefore detrimentally causing bystander damage to surrounding cells and tissues. On the other hand, recent evidence supports the notion that an active complement pathway is a necessity for the normal maintenance of the neurosensory retina. In this scenario, complement activation appears to have beneficial effect as it promotes cell survival and tissue remodeling by facilitating the rapid removal of dying cells and resulting cellular debris, thus demonstrating anti-inflammatory and neuroprotective activities. In this review, we discuss both the beneficial and detrimental roles of CS in degenerative retina, focusing on the diverse aspects of CS functions that may promote or inhibit macular disease.
    Research Journal of Immunology 09/2014; 2014:483960. DOI:10.1155/2014/483960
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