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

Jun 20, 2008The Journal of neuroscience : the official journal of the Society for Neuroscience

Lack of Complement C3 speeds up amyloid plaque buildup, brain cell loss, and changes immune cell behavior in mice with Alzheimer's-like protein

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Abstract

At 17 months of age, APP;C3(-/-) mice exhibited up to twofold increased amyloid plaque burden compared to age-matched APP transgenic mice.

No significant differences in neuropathology were observed between APP;C3(-/-) and APP transgenic mice at 8 and 12 months.
APP;C3(-/-) mice showed significantly increased levels of total amyloid beta and fibrillar amyloid plaques in the midfrontal cortex and hippocampus at 17 months.
Increased levels of TBS-insoluble amyloid beta(42) and reduced levels of TBS-soluble amyloid beta(42) and amyloid beta(40) were found in brain homogenates of APP;C3(-/-) mice.
There was a trend for increased amyloid beta levels in plasma from APP;C3(-/-) mice.
A significant loss of neuronal-specific nuclear protein-positive neurons was observed in the hippocampus of APP;C3(-/-) mice.
APP;C3(-/-) mice exhibited differential activation of microglia, indicating a shift toward a more alternative phenotype.

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

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