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The Journal of Neuroscience, June 18, 2008, 28(25):6333-6341; doi:10.1523/JNEUROSCI.0829-08.2008

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

Marcel Maier,^1 * Ying Peng,^1 * Liying Jiang,¹ Timothy J. Seabrook,¹ Michael C. Carroll,² and Cynthia A. Lemere¹

¹Center for Neurologic Diseases, Brigham and Women's Hospital, and ²Center for Blood Research Institute for Biomedical Research and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to Dr. Cynthia A. Lemere, Center for Neurologic Diseases, Harvard New Research Building, Room 636F, 77 Avenue Louis Pasteur, Boston, MA 02115. Email: clemere{at}rics.bwh.harvard.edu

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 β (Aβ) 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 Aβ and fibrillar amyloid plaque burden in midfrontal cortex and hippocampus, which correlated with (1) significantly increased Tris-buffered saline (TBS)-insoluble Aβ₄₂ levels and reduced TBS-soluble Aβ₄₂ and Aβ₄₀ levels in brain homogenates, (2) a trend for increased Aβ 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.

Key words: Alzheimer's disease; amyloid β; Aβ peptide; complement; C3; neurodegeneration

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Received Oct. 30, 2007; revised April 23, 2008; accepted May 1, 2008.

Correspondence should be addressed to Dr. Cynthia A. Lemere, Center for Neurologic Diseases, Harvard New Research Building, Room 636F, 77 Avenue Louis Pasteur, Boston, MA 02115. Email: clemere{at}rics.bwh.harvard.edu

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