Endogenous apolipoprotein E suppresses LPS-stimulated microglial nitric oxide production

Abstract

The human apolipoprotein (apo) E4 isoform is associated with an increased risk for Alzheimer's disease (AD) and poor prognosis after acute CNS injury. Addition of human apoE inhibits murine microglial activation in culture, suggesting that microglia might be an important physiological target of apoE. In the present study, we examined the role of endogenous murine apoE in modulating microglial nitric oxide (NO) production following lipopolysaccharide (LPS) stimulation. Brain cultures from apoE-deficient mouse pups showed enhanced NO production relative to cultures from wild-type mice and from transgenic mice expressing the human apoE3 isoform, demonstrating that endogenous apoE produced by glial cultures is capable of inhibiting microglial function. ApoE produced within the brain may suppress microglial reactivity and thus alter the CNS response to acute and chronic injury.

Apolipoprotein E and Neurological Disease: Therapeutic Potential and Pharmacogenomic Interactions

“…A fundamental role for apoE in modifying glial activation would also be relevant in chronic neurodegenerative disease in which glial activation exacerbates neuronal injury. Consistent with this hypothesis, several in vitro studies have demonstrated that biologically relevant concentrations of apoE modify astrocyte and microglial activation and secretion of inflammatory mediators [41,43,44,56,[61][62][63]. Isoform-specific immunomodulatory effects of apoE were suggested by observations that apoE3 suppressed secretion of tumor necrosis factor (TNF)-α in a human microglial cell line to a greater extent than apoE4 [64].…”

Apolipoprotein E ε4 is associated with rapid progression of multiple sclerosis

“…The APOE gene product has been shown to be a determinant of increased microglial activation in AD. 24 Such activation may also be a central element of demyelination in MS. 25 Differential effects of APOE on free radical damage via nitric oxide 26,27 as well as against hydrogen peroxide toxicity 28 have been reported. APOE has also been shown to suppress lymphocyte activation 29 and to inhibit the glial secretion of tumor necrosis factor-alpha.…”

Human C-reactive protein slows atherosclerosis development in a mouse model with human-like hypercholesterolemia

“…Furthermore, Apoe Ϫ/Ϫ mice are in a continuous state of low-grade systemic inflammation (10), and the apoE protein per se can alter immune responses (11). Thus, the Apoe Ϫ/Ϫ mouse model may not be ideal for studies of hCRP in atherosclerosis.…”