APOE3 and APOE4 binding to macrophages triggers inositol (1,4,5-) triphosphate-mediated increases in intracellular calcium

Apolipoprotein E (apoE) is a 34 kDa protein that mediates binding of lipopro teins to the LDL and LRP receptors- Apart from maintaining plasma cholesterol homeostasis, apoE may participate in mobilization and redistribution of lipids during normal development of the nervous system, in the regeneration of peripheral nerves after injury, and growth and differentiation of smooth muscle and endothelial cells. ApoE4 may be associated with an increased risk of developing sporadic and late-onset familial Alzheimer's disease and poor prognosis after acute brain injury. To understand the role of apoE in normal and diseased processes, we have examined the effects of binding of apoE3 and apoE4 on changes in inositol (1,4,5-) triphosphate (IP;i) and intracellular calcium ([Ca2+])i in murine peritoneal macrophages. Binding of both apoE.'i and apoE4 increased in a dose-dependent manner the generation of IP,-), and intracellular calcium. As judged by changes in ([Ca2+]), apoE3 and apoK4 did not compete for binding with cM-methylamine or a receptor binding fragment of rt2M, and with lactoferrin. ApoE3 and apoE4-induced increases in ([Ca2-|-]), were not affected by receptor associated protein or pertussis toxin. We suggest that apoE3 and apoE4, in addition to binding to the I.DL/LRP receptor system, also binds to a novel unidentified receptor on macrophages which results in the generation of several second messengers, and these second messenger;may be involved in some of the biological effects of apoK.'J and K-i in health and diseased processes.

Duke Scholars

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