Neuroprotective Effect of Apolipoprotein D against Human Coronavirus OC43-Induced Encephalitis in Mice

Abstract

Apolipoprotein D (apoD) is a lipocalin upregulated in the nervous system after injury or pathologies such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. We previously demonstrated that apoD protects against neuropathology by controlling the level of peroxidated lipids. Here, we further investigated the biological function of apoD in a mouse model of acute encephalitis. Our results show that apoD transcript and protein are upregulated during acute encephalitis induced by the human coronavirus OC43 (HCoV-OC43) infection. The apoD upregulation coincides with glial activation, and its expression returns to normal levels when the virus is cleared, concomitantly to a resolved glial reactivity. In addition, the overexpression of human apoD in the neurons of Thy-1/ApoD transgenic mice results in a threefold increase of the number of mice surviving to HCoV-OC43 infection. This increased survival rate is correlated with an upregulated glial activation associated with a limited innate immune response (cytokines, chemokines) and T-cell infiltration into infected brains. Moreover, the protection seems to be associated with a restricted phospholipase A2 activity. These data reveal a role for apoD in the regulation of inflammation and suggest that it protects from HCoV-OC43-induced encephalitis, most likely through the phospholipase A2 signaling pathways.

Modulation of Apolipoprotein D levels in human pregnancy and association with gestational weight gain

“…Another argument against ApoD transcriptional downregulation is the presence of oxidative and inflammatory markers mostly in complicated but also in normal pregnancies [47]. Oxidative stress [26-29] and inflammation [25,26] were both reported as intensifying ApoD mRNA production. ApoD decrease could also be caused by the inhibition of its translation or the increase of its degradation rate.…”

“…ApoD expression is modulated in many situations (for review see [14,15]), namely cellular growth and differentiation [16-19], cancer [19,20], nervous system pathologies [21-24] inflammation [25,26] and oxidative stress [27-29]. ApoD is also involved in gestation and fetus development.…”

Apolipoprotein D: An overview of its role in aging and age-related diseases

“…In addition, Do Carmo et al showed conclusively that ApoD overexpression is sufficient to temper inflammation observed in coronavirus-induced encephalitis. 63 The study of mutant mice in similar conditions would also greatly inform our current understanding of some of ApoD’s physiological functions.…”

Apolipoprotein D in lipid metabolism and its functional implication in atherosclerosis and aging

“…This effect seems to be mediated by the NF-kB pathway, as there are several conserved NF-kB binding sites in the apoD promoter [66]. Furthermore, Do Carmo et al [67] show that apoD confers a neuroprotective effect in the brain of mice. Their studies demonstrate that mice over-expressing human apoD in neurons, as opposed to normal controls, are more resistant with a 3-fold higher survival rate in response to human coronavirus-induced acute encephalitis.…”