Abnormal tau phosphorylation is reduced in genetically complement-inhibited P301L tau transgenic mice. A, Simplified illustration of activation of the complement cascade in mice and its hypothetical effect on tau phosphorylation in the brain. Spontaneous (alternative pathway) or antibody-mediated (classical pathway) activation can initiate the complement cascade in the aging brain and if insufficiently controlled by inhibitory proteins (for example, Crry on C3 convertases or CD59a in the terminal pathway in mice) this can lead to the formation of a self-integrating membrane pore formed by C5b-9, also known as the membrane attack complex (MAC). The MAC disrupts cellular homeostasis by sublytic or lytic mechanisms potentially leading to activation of kinases, which could contribute to phosphorylation of tau protein. B, Examples of high and low tau pathology in various brain regions of 15 to 20 months aged P301L tau or P301L tau/sCrry transgenic mice, respectively, as detected by immunoreactivity of phospho-tau specific antibody AT8. C, Number of AT8-positive cells in the brainstem of 15 to 20 months aged tau (n = 13) and tau/sCrry (n = 17) transgenic mice. Each symbol indicates the mean from 5 to 6 sections per mouse (solid line is the group mean). The proportion of mice that developed tau pathology above the overall mean (dashed line) was significantly higher in tau mice than in the complement-inhibited tau/sCrry transgenic mice (2×2 contingency table, two-tailed Fisher’s exact test). D, Immunoreactivity for microglia marker CD68 in the brainstem of the two mice shown in B. E, Average number of AT8-positive cells in the brainstem plotted against % area of CD68 immunoreactivity in the same brain area. Linear regression with trend line (solid line) and 95% confidence intervals (C.I., dashed lines) are indicated; r2 as goodness-of-fit is significant (95% C.I. for the slope and P = 0.0001, two-tailed F test). Scale bar, 100 μm.