Potential Roles for apoE and apoJ in CNS Disease

Further studies to understand the structure and function of apoE and apoJ-containing lipoproteins produced by cells within the brain is likely to provide important insights into the role of these proteins in neurodegenerative and other diseases of the CNS. This issue will be considered in regard to Alzheimer's disease (AD) and brain repair following CNS injury. Genetic epidemiological studies have shown that the e4 allele of apoE is a major risk factor for AD.43 In addition, recent data suggests that apoE4 is also a risk factor for poor outcome after head trauma,44,45 cerebral hemorrhage,46 cardiac bypass,47 and possibly stroke.48 ApoE4 also appears to influence the age of onset of Parkinson's disease.49 In regard to AD, one hypothesis is that the association between apoE4 and AD is due to the ability of apoE to interact with the Ap protein. Ap deposition in the AD brain appears to be an early and important pathogenetic event in AD.50 A recent in vivo study highlights the potential importance of both apoE and apoJ in Ap deposition. Mice have recently been developed in which overexpression of a mutant form of the amyloid precursor protein (APP) results in age-dependent Ap deposition in plaque-like structures resembling those found in AD.51 Bales et al52 found that there was a marked decrease in Ap deposition and thioflavin-S-positive amyloid deposits when the mutant APP transgenic mice were bred onto a mouse apoE-/- background. This finding suggests that the presence of mouse apoE promotes Ap deposition through increasing Ap fibrillogenesis or inhibiting its clearance. Interestingly, the other major apolipoprotein produced in brain outside of apoE is apoJ, and apoJ like apoE has been shown to bind to Ap both in vivo and in vitro.53-55 Since apoE and apoJ are both present in lipoprotein particles in brain and CSF, this suggests that important interactions influencing Ap metabolism may occur between Ap, apoE, and apoJ in CNS lipoprotein particles. In fact, recently published data suggests that:

1) Ap in CSF is found in HDL-like lipoproteins56 and

2) apoE and apoJ associate with Ap in CSF.53-55

It will be important in future studies to characterize the interaction between apoE, apoJ, and Ab in lipoprotein particles likely to be found in brain, such as those derived from astrocytes. This is highlighted by studies which have shown that while lipid free apoE isoforms can interact with Ap,57,58 cell secreted apoE isoforms containing lipid-interact with Ab in a different isoform-specific fashion.59,60 Studies examining apoE, apoJ, and Ap interactions under physiological conditions may give insight into mechanisms underlying Ap deposition.

ApoE and apoJ-containing CNS lipoproteins may also play a role in modulation of CNS lipid metabolism and impact on recovery after CNS injury. Several in vitro studies suggest that apoE3-containing lipoproteins can enhance neurite outgrowth, whereas apoE4 either has no effect or decreases neurite outgrowth.61,62 Similar findings have also been made using astrocyte-derived apoE-containing lipoproteins and primary hippocampal neurons.35,36 While apoJ is also present in these astrocyte-secreted particles, it is unclear if it plays a role in neurite outgrowth. Some studies have suggested that the effects of apoE-containing lipoproteins on neurite outgrowth require neuronal LRP.36,62-64 This implies that uptake of lipoprotein particles containing cholesterol and phospholipids may be required for this effect. While the mechanism of this LRP-mediated effect is unclear, these in vitro findings suggest the hypothesis that following CNS injury or in a CNS disease, apoE-containing lipoproteins may facilitate cholesterol/lipid delivery and utilization in regenerating neuronal processes. For example, it was reported that reactive synaptogenesis following a dernervating hippocampal lesion is enhanced by estrogen in ovariectomized wild type mice. This enhancement by estrogen was not observed in apoE-/- mice.65 In addition to the potential role of apoE/apoJ in cholesterol lipid delivery in the CNS, another important role they may play is in "reverse cholesterol transport". This is suggested by our recent data showing that nascent rat astrocyte-secreted lipoproteins are cholesteryl ester-poor lipoproteins shaped like discs. Our recent in vivo study also supports this potential role of apoE in CNS following injury. We showed that following a hippocampal denervating lesion, that apoE-/- mice cleared lipid-laden axonal debris much more slowly than wild type mice.66 If there are isoform, specific differences in the ability of apoE to clear cholesterol and lipid following CNS injury, this could impact on neurologic outcome. Studying the physiological form and functions of apoE/apoJ lipoproteins produced in CNS will be critical in further characterizing the role of these proteins in lipid metabolism following CNS injury.

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