. 2022 Aug 10;13:970486. doi: 10.3389/fimmu.2022.970486

Table 1.

Descriptive comparison of the effects of complement inhibition in AD and MS animal models.

ALZHEIMER’S DISEASE MODELS			MULTIPLE SCLEROSIS MODELS
Inhibition	Mice model	Effect	Inhibition	Animal model	Effect
C1q -/-	APP	Decreased phagocytic microglia and synapse loss. Prevention of synaptic Aβ oligomer toxicity, increased hippocampal LTP ⁽²⁰⁾	C1q -/-	MOG_35-55 induced EAE mice	Density of Iba1+ cells, microglia with reactive gliosis morphologies, expression of DAM marker CLEC7A lower in C1q -/- mice. No effect on disease phenotype ⁽¹³⁸⁾
	APP APP/PS1	Comparable total and fibrillary Aβ, lower level of periplaque activated glia. Lower decline in synaptophysin and MAP2 in hippocampus CA3 ⁽¹¹⁹⁾
	3xTgBUB (APP Swedish, P301L Tau, PSN1 mutation)	C1q addition in cultures protected neurons against fibrillary and oligomeric Aβ toxicity. Enhanced Aβ aggregation outside the cell. Effect mediated by LRP1B, GPR6 ⁽¹²¹⁾
C1 blocking antibody	Tau P301S	Inhibition of microglial engulfment of synapses and prevention of decline in synapse density ⁽¹²⁰⁾	ANX-M1.21 (C1q blocking antibody)	MOG_35-55 induced EAE mice	Decreased Iba1+ and Iba1+/FTL+ microglia ⁽¹³⁸⁾

C3 -/-	Tau P301S	Decreased neuron loss, brain atrophy, improved neurophysiological and behavioral measurements ⁽¹¹⁴⁾	CVF (depletes C3)	Myelin + CFA immunized Lewis rats	CVF given at day 9 delayed onset of EAN by 2-3 days, when given at days 9-12 delayed onset by 4-5 days ⁽¹³²⁾
	PS2/APP	Rescued plaque associated synapse loss ⁽¹¹⁴⁾	CVF (depletes C3)	BPN myelin immunized rats	Lower clinical scores, less demyelination. Fewer ED1-positive macrophages, CD11bc-positive cells ⁽¹³³⁾
	C57BL/6J	Absence of age-dependent synapse and neuron loss in hippocampal CA3; significantly enhanced LTP and cognition, less anxiety ⁽²¹⁵⁾	C3-/-	MOG_35-55 induced EAE mice	In both C3 -/- and factor B -/- mice, little infiltration of the parenchyma by macrophages and T cells, protection from demyelination ⁽¹³⁵⁾
	hAPP	Decreased phagocytic microglia, decreased early synapse loss ⁽²⁰⁾			Mice equally susceptible to EAE. No differences in production of proinflammatory cytokines (IL-2, IL-4, IL-12, TNF-a, and IFN-y) ⁽¹³⁶⁾
	hAPP	Increased total and fibrillary Aβ plaque burden, insoluble Aβ42, plasma Aβ, loss of neuronal-specific NPP+ neurons in hippocampus, activation of microglia to alternative phenotype (CD45+, decreased CD68) ⁽¹¹⁷⁾
sCrry (C3 inhibitor)	hAPP	Increased Ab deposition (2-3x), accumulation of degenerating neurons ⁽¹¹⁸⁾	CR2-Crry	MOG_35-55 induced EAE mice	Synaptic preservation in LGN where CR2-Crry AAV injected. Reduced synaptic terminal engulfment within microglial lysosomes. Visual acuity preservation. No effect on demyelination, axonal loss, gliosis, myelin engulfment ⁽⁵⁷⁾
sCrry (C3 inhibitor)	hAPP		CR2-Crry	MOG_35-55 induced EAE mice	Administration prior to and during onset of EAE attenuates both MOG-induced and transferred EAE in CR2-Crry and CR2-factor H treated mice ⁽⁹⁹⁾

C3aR-/-	Tau PS19	Tau pathology rescue, amelioration of synaptic impairment and neuronal loss. Reversed disease-associated microglia phenotype and A1 astrocytosis. Effects mediated by signaling pathway involving STAT3 ⁽¹²⁵⁾	C3aR -/- C3a CNS expression	MOG_35-55 induced EAE mice	C3aR -/- attenuated chronic EAE, modestly reduced macrophage and T cell infiltrates in the SC. Selective C3a-GFAP expression exacerbated chronic EAE, mortality, increased macrophage and T cell infiltrates ⁽¹⁷²⁾
C3aR-/-	Tau PS19		Dual C3aR -/- C5aR -/-	MOG_35-55 induced EAE mice	Delayed onset of disease but no attenuation of disease severity. Greater infiltration of CD4+ T cells ⁽¹⁷³⁾

C5aR -/-	Arctic APP	Prevention of behavioral deficits. Absent CCR2+ monocytes/macrophages near plaques. Rescue of neuronal complexity. Decreased inflammatory microglia ⁽¹²³⁾	C5aR -/-	MOG_35-55 induced EAE mice	Mice fully susceptible to MOG-induced EAE, no difference in disease onset or severity. Similar macrophage and T cell infiltrates. Equal proinflammatory gene expression ⁽¹⁷¹⁾
			C5 -/-	Guinea pig myelin + incomplete Freund’s adjuvant immunized mice	Acute EAE: Delay in inflammatory cell infiltrates and tissue damage Chronic EAE: Axonal depletion and severe gliosis in C5 -/-. Extensive remyelination in C5-sufficient mice ⁽¹⁴⁶⁾
			C5 -/-	Myelin-induced EAE mice	Increased TUNEL + apoptotic cells in C5 -/- mice during clinical recovery (lymphocytes, monocytes, OLG) ⁽¹⁴⁷⁾
PMX205 (C5aR1 inhibitor)	Tg2576 3xTg	Reduction of fibrillar amyloid deposits, activated glia. In Tg2576 mice, improvement in behavioral tasks with reduction in pathology. In 3xTg, inhibition also reduced hyperphosphorylated tau ⁽¹²⁴⁾	PMX205 (C5aR1 inhibitor)	Biozzi AB/H mice (syngeneic Biozzi AB/H spinal cord homogenate + CFA)	Amelioration of progressive neurological disability (not complete rescue). Reduction of NLPR3 inflammasome, upregulation of PPAR ⁽¹⁴³⁾
PMX205 (C5aR1 inhibitor)	Tg2576 3xTg		AcF-[OPdChaWR] (C5aR inhibitor)	EAE: gpBMP + CFA immunized rats ADEAE: Additional injection of Z12 (anti-myelin) mAb	Neutrophil response to C5a blocked. No effect on clinical disease or pathology ⁽¹⁷⁰⁾

Green coloring represents a beneficial effect of complement inhibition, while orange coloring implies an overall detrimental or null effect of inhibition. Although most studies appear to suggest a beneficial role of C1q and C3 inhibition in AD and MS models, others imply that these factors may exert some protective functions in these conditions. While complement chemokine inhibition (C3a, C5a) was largely protective in AD, the beneficial effects of this inhibition in MS models have been more controversial.