Nerve injury stimulates the secretion of apolipoprotein E by nonneuronal cells.

Abstract

Nerve trauma initiates significant changes in the composition of proteins secreted by nonneuronal cells. The most prominent of these proteins is a 37-kDa protein, whose expression correlates with the time course of nerve development, degeneration, and regeneration. We now report that the 37-kfla protein is apolipoprotein E (apoE). We produced a specific antiserum against the 37-kDa protein isolated from previously crushed nerves. This antiserum recognizes a 36-kDa protein in rat serum that we have purified and identified as apoE. The anti-37-kDa antiserum also recognizes apoE on electrophoretic transfer blots of authentic samples of high and very low density lipoproteins. The nerve 37-kDa protein comigrates with apoE by two-dimensional electrophoresis, shares a similar amino acid composition, and reacts with an antiserum against authentic apoE. The purified apoE specifically blocks the immunoprecipitation of [35S~methionine-labeled 37-kDa protein synthesized by nonneuronal cells. Thus, on the basis of its molecular mass, isoelectric point, amino acid composition, and immunological properties, we conclude that the 37-kDa protein is apoE. We also used light microscopic immunohistochemistry to localize apoE following nerve n'jury. In rats with optic nerve lesions, the 37-kDa antiserum bound specifically to the degenerating optic tracts and to the retinorecipient layers of the lateral geniculate nucleus and the superior colliculus. We propose that apoE is synthesized by phagocytic cells in response to nerve injury for the purpose of mobilizing lipids produced as a consequence of axon degeneration.Nonneuronal cells in the mammalian nervous system are estimated to outnumber neurons by 10:1 and may account for nearly half of the volume of the brain (1). Although the functions of some nonneuronal cells [which include astrocytes, oligodendrocytes, and microglia in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS)] are beginning to be understood, thus far little is known at the molecular level of the roles such cells play in the development and in the normal functioning of the nervous system or in response to injury. Recently, it has been shown that nonneuronal cells in the PNS and CNS release soluble proteins into their microenvironment during development (2-4) and following nerve injury (3-5). The fact that the synthesis and secretion of some of these proteins is significantly enhanced during nerve regeneration in the PNS leads naturally to the hypothesis that they may play an important role in determining the ability of an axon to regenerate following injury. The poor regenerative response of most CNS neurons in higher vertebrates might be related to the failure of CNS nonneuronal cells to secrete the requisite proteins necessary for regeneration or the failure to secrete them in sufficient amounts. These considerations serve to emphasize the importance of identifying and characterizing the proteins released by nonneuronal cells in the PNS and CNS and of elucidating how t...

The distribution of apolipoprotein E in mouse olfactory epithelium

“…It is primarily synthesized in the liver, but is also expressed in significant amounts in the nervous system. Previous studies have shown apoE mRNA and protein increase at the site of neural regeneration and that apoE containing lipoproteins stimulate neurite outgrowth in a variety of neuronal cultures (Bellosta et al, 1995;Holtzman et al, 1995;Ignatius et al, 1987;LeBlanc and Poduslo, 1990;Nathan et al, 1994;Nathan et al, 1995;Nathan et al, 2001;Nathan et al, 2002;Nathan et al, 2004;Snipes et al, 1986;Teter et al, 1999;White et al, 2001). We have previously shown that apoE surrounds glomeruli of the olfactory bulb (OB) (Struble et al, 1999).…”

Transport and Retinal Capture of Lutein and Zeaxanthin with Reference to Age-related Macular Degeneration

“…It has been shown that, in both the central and peripheral nervous systems, ApoE expression by astrocytes is up-regulated in response to neuronal injury and neuro-degenerative disease. 58,66,80 Indeed, there is evidence for ApoE up-regulation by Mü ller cells in degenerating human retina, where increased ApoE immuno-reactivity is found in the sub-retinal space of detached retinas 73 and in the Mü ller cells of retinas affected by glaucoma or AMD. 51 Furthermore, the relatively high levels of ApoE mRNA detected in the retina, especially in the eyes of older donors and in an individual with documented AMD, support the view that up-regulation by retinal glia may be responsible for the observed increase in ApoE expression.…”

Transcription Factors Zic1 and Zic2 Bind and Transactivate the Apolipoprotein E Gene Promoter

“…In the human brain, the synthesis occurs both in glial cells and in subpopulations of neurons in the cortex and hippocampus (4). A number of previous in vitro and in vivo studies as well as recent experiments with apoEdeficient mice and human APOE transgenic mice reveal that apoE plays an important role in neuronal maintenance and repair (5)(6)(7)(8)(9)(10)(11)(12). Genetic studies have identified the apoE4 allele as a major risk factor for developing Alzheimer's disease (AD), both in sporadic and in familial late onset forms of the disease (13,14).…”