(1) RNA levels of complement components (C4b, C1qa, C1qb, and C1qc), DAMP receptors (i.e., Tlr2, Tlr4, Tlr8, C3ar1 and C5ar1) were upregulated in the thalamus and the whole brain. (2) TLR2 deficient, but not C3aR deficient and C5aR deficient, caused higher susceptibility to prion disease. (3) TLR2 deficient or C5aR deficient did not alter the transcription of proinflammatory genes. Here, C4B is linked to prion disease.