ApoE-deficient promotes blood-brain barrier disruption in experimental autoimmune encephalomyelitis via alteration of MMP-9.

Disruption of the blood-brain barrier (BBB) is a surrogate marker of acute inflammatory lesions in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Data from experiments suggest that apolipoprotein E (ApoE) plays an important role in the antiinflammatory and immunological process in MS/EAE. Recent researches have shown that lack of ApoE leads to loss of cerebrovascular integrity and BBB breakdown causing neuronal injury. Cerebrovascular effects of ApoE might be another important element resulting to more susceptibility to MS/EAE. However, there is no direct evidence that ApoE dependently contributes to maintaining BBB integrity in EAE. In this study, we induced EAE in ApoE-/- mice and wild-type mice. During EAE, our results show that lack of ApoE increased the Evan's blue (EB) permeability of BBB. Furthermore, deficiency of ApoE upregulated MMP-9 expression activity but decreased the expression of endothelial cell tight junction integral proteins claudin-5 and occludin. Our result also suggests that the protective role of ApoE in EAE by maintaining BBB integrity could be another interesting therapeutic target at MS/EAE.

Apolipoprotein E and its mimetic peptide suppress Th1 and Th17 responses in experimental autoimmune encephalomyelitis.

Apolipoprotein E (apoE) has been detected to possess anti-inflammatory properties that can contribute to protection against experimental autoimmune encephalomyelitis (EAE). However, its impact on Th1 and Th17 responses in EAE is unclear. In this study, we induced EAE in apoE-/- mice and wild-type mice. We observed that the absence of apoE resulted in the increased proportion of Th1 and Th17 cells in the spleens and brains, as well as up-regulated expressions of proinflammatory cytokines (IL-17, IFN-γ, TNF-α, IL-12, IL-1ß and IL-6) and transcription factors (RORγt and T-bet) in the CNS. ApoE-/- mice also showed the increased release of proinflammatory cytokines by macrophages in vitro. In addition, we used a mimetic peptide of apoE, which mimic the functions of apoE except for lipid transport. ApoE mimetic peptide could reverse the above negative effect in EAE. Thus, apoE can modulate Th1 and Th17 responses, likely through its inhibitory effect on the secretion of cytokines by macrophages. Our result also suggests that apoE mimetic peptide might be developed into a therapeutic agent for multiple sclerosis.