Oxidized Low-Density Lipoprotein Is Present in Astrocytes Surrounding Cerebral Infarcts and Stimulates Astrocyte Interleukin-6 Secretion

Abstract

Ischemic injury to brain is associated with both disruption of the blood-brain barrier and increased oxidative stress. Given the neurotoxicity associated with exposure to oxidized low-density lipoprotein (oxLDL) in vitro, we tested the hypothesis that oxLDL may be present in parenchymal cells of cerebrum after infarction and that oxLDL may influence the pathophysiology of cerebral infarction. Our results showed that the subacute phase of cerebral infarction in patients was characterized by the appearance of oxLDL epitopes in astrocytes, but not neurons or microglia, in the perinecrotic zone. We further demonstrated that minimally oxLDL was most effectively internalized by primary cultures of rat astrocytes, and that exposure to minimal oxLDL stimulated astrocyte interleukin-6 secretion but did not alter nitric oxide production. These results demonstrate for the first time that oxLDL is present in brain parenchyma of patients with ischemic infarction and suggest a potential mechanism by which oxLDL may activate innate immunity and thereby indirectly influence neuronal survival. Lipoproteins are complex structures that orchestrate lipid trafficking through direct interaction with cell membranes and through receptor-mediated processes with apolipoproteins. Low-density lipoprotein (LDL) and its major apolipoprotein, apoB, are prone to oxidation in circulation and the resultant oxidized (ox)LDL is thought to be a key element in atherogenesis.1 Increasing evidence shows that oxLDL is internalized by or activates cell-surface receptors on endothelial cells, vascular smooth muscle cells, and monocytes/macrophages, and thereby alters several cellular functions that can culminate in cell death.2 Indeed, oxLDL is cytotoxic to many cell types in culture primarily through these receptor-dependent processes. Importantly, the pathophysiology of oxLDL is much more complicated than simply inducing death in cultured cells; oxLDL also affects leukocyte adhesion, motility of various cell types, growth factor production, and activation of innate immunity. In our original description of central nervous system (CNS) lipoproteins from patients with Alzheimer's disease (AD), we detected disease-related changes in lipids that are consistent with increased oxidation of CNS lipoproteins compared to age-matched controls. 4 We subsequently demonstrated that minimally oxidized human cerebrospinal fluid lipoproteins are toxic to cultured neurons, establishing that oxidation of lipoproteins normally residing in the CNS is capable of inducing neuron cell death in culture. 5,6 Similarly, others have demonstrated neuronal cytotoxicity from oxLDL. Specifically, oxLDL mediates time-and dose-dependent cytotoxicity to primary cultures of embryonic rodent cerebral and hippocampal neurons but not astrocytes or microglia. 7,8 Unlike experiments with minimally oxidized cerebrospinal fluid lipoproteins, these experiments with oxLDL did not include characterizing the extent of LDL oxidation, a variable known to significantly impact biological activity.The C...

Circulating Lp-PLA2 activity correlates with oxidative stress and cytokines in overweight/obese postmenopausal women not using hormone replacement therapy

“…Aging and visceral fat accumulation play important roles in LDL atherogenicity including increased LDL oxidation and smaller LDL particle size, and oxidative stress activates inflammation and cytokine expression (Paik et al 2012a, b;Chae et al 2011;Hyun et al 2008). Ox-LDL modifies IL-6 secretion (Shie et al 2004;Shi et al 2007) and stimulates Lp-PLA 2 expression in monocytes through the phosphatidylinositol 3-kinase and p38 mitogen-activating protein kinase pathways (Wang et al 2010). Lp-PLA 2 is preferentially associated with small dense LDL (Tsimihodimos et al 2002) and cleaves the oxidized phosphatidylcholine contained in the ox-LDL into two inflammatory mediators: lysoPC and oxidized free fatty acids (Macphee et al 1999).…”

Nuclear Factor-κB Activation and Postischemic Inflammation Are Suppressed in CD36-Null Mice after Middle Cerebral Artery Occlusion

“…On the other hand, cerebral ischemia is well known to produce numerous species of modified lipids (Adibhatla et al, 2006). For example, modified low-density lipoprotein (LDL), such as oxidized LDL, is formed after cerebral ischemia and could activate CD36 (Uno et al, 2003;Shie et al, 2004;Vibo et al, 2007). In addition, hypoxia has been reported to produce diacylglyceride, a CD36 ligand that is involved in inflammatory signaling via toll-like receptors 2/6 (TLR2/6; see below) (Bruder et al, 2005;Hoebe et al, 2005).…”

Microglial Activation Induced by Neurodegeneration

“…The cultures were changed back to fresh medium 3 days later. Purity of neurons was assessed by counting cells stained with various antibodies (16,20) as follows. 1) Neurons were stained with the monoclonal anti-neuron-specific nuclear protein (NeuN) (Chemicon, Temecula, CA).…”