TABLE 1.5.

Interactions between complement and prion proteins in the CNS.

	Pathogen (disease)	Study design	Outcomes	Conclusion	References
1	Scrapie (Prion disease)	(in vivo) Prion disease model: scrapie-infected mice	(1) FB and FP (properdin) levels significantly increased in the brain of scrapie-infected mice. (2) FB and C3 colocalization was observed with neurons and activated microglia, but not with astrocytes.	The alternative pathway is activated and plays a role in triggering the complement cascade in the brain during prion infection-induced neuropathogenesis.	Chen et al., 2020
2	Human sCJD and scrapie	(1) (Human) Postmortem sCJD brain specimens (2) (in vivo) Prion disease model in mice (WT vs. Triple deficient lacking TNF-α, IL-1α and C1qa)	(1) C3+-astrocytes (A1-like-astrocytes) were abundant in mouse and human prion diseases. (2) Mice lacking TNF-α, IL-1α and C1qa had accelerated prion disease course (measured by survival rate) without affecting the formation of PrPSc and microglial activation. (3) C3 expression was significantly up-regulated and C3+-astrocytes significantly increased in the thalamus of terminally sick WT but not in Triple deficient mice.	Reactive astrocyte signature in prion diseases is characterized by upregulation of C3 and a mixed A1/A2 phenotype, which is distinct from other neurodegenerative diseases. C3 expression in astrocytes may be protective in prion disease.	Hartmann et al., 2019
3	Scrapie (Prion disease)	(in vivo) Prion disease model: scrapie infection in mice (WT, TLR2 deficient, C3aR deficient, and C5aR deficient).	(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.	(a) Scrapie infection induced enhanced expression of complement components (C4b and C1q) as well as anaphylatoxin receptors (C3aR and C5aR). (b) C3aR or C5aR signaling does not play a major role in prion diseases.	Carroll et al., 2018
4	Scrapie (Prion disease)	(in vivo) FH deficient mouse prion disease model (scrapie) using transgenic mice expressing zero (FH–/–), one (FH+/–), or two (FH+/+) allelic copies of Cfh.	(1) Brain PrP loads correlated with Cfh expression. (2) Splenic propagation and clinical manifestation were delayed by FH deficiency. (3) FH directly interacts with PrPSc.	(a) FH enhances scrapie-induced brain prion load. (b) FH directly binds prions.	Kane et al., 2017
5	Human sCJD	(Human) CSF from prion disease patients and non-prion disease patients.	(1) Complement hemolytic activity (CH50) was lower in the CSF from sCJD patients. CH50 was consistently lower in genetic prion disease patients. (2) C3, C4, and C9 protein levels were lower in the CSF from sCJD patients.	Complement activity is down-regulated in the CSF of CJD patients, conceivably through consumption.	Chen et al., 2016
6	Scrapie (prion disease)	(in vivo) Prion disease model (scrapie) in mice and hamster: 139A-infected mice and 263K-infected hamster	(1) Total complement activity (CH50) was higher in the brain of scrapie-infected rodents. (2) C1q was upregulated in the brain of scrapie-infected rodents. (3) Stronger C3 signals in scrapie-infected brain. C3 colocalized with astrocytes, microglia, and neurons. (4) MAC was deposited in the infected brain and colocalized with neurons.	The activation of the complement system may be a hallmark during prion infection.	Lv et al., 2014
7	Scrapie (prion disease)	(in vivo and in vitro) Scrapie (Chandler and 22L) infection model: mice and N2a cells.	(1) C1q colocalized with PrP in Chandler-infected N2a cells, while C3 colocalized with PrP in 22L-infected N2a cells. (2) C1q colocalized with PrP throughout the brain and mild C3 deposition was detected in the cerebral cortex, septum, thalamus, midbrain, and pons in Chandler-infected brain. C1q was absent in the dorsal part of thalamus and C3 was more pronounced in the thalamus compared to Chandler-infected brain.	Prion-induced complement activation is PrP strain dependent.	Hasebe et al., 2012

The relevant complement proteins are highlighted in bold.