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

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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Updated Mar 29, 2026

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.

Simplified

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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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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