Ceramide Is Responsible for the Failure of Compensatory Nerve Sprouting in Apolipoprotein E Knock-Out Mice

Abstract

Apolipoprotein E (apoE) is a key transporter of the cholesterol and phospholipids required for membrane synthesis and nerve growth. We now report a virtual absence in apoE knock-out (KO) mice of normal nerve growth factor (NGF)-driven compensatory sprouting of undamaged cutaneous nociceptive nerves. In contrast, NGF-independent regeneration of crushed axons was unaffected. Essentially similar results came from aged wild-type mice. In apoE KO mice, the endogenous sprouting stimulus was suspect, because NGF administration induced normal sprouting; nevertheless, NGF increased normally in denervated skin, transported normally in the axons, and led to phosphorylation of trkA, erk1, and erk2. However, sprouting was restored in apoE KO mice (although not in aged mice) by fumonisin B1, an inhibitor of ceramide synthesis. A shotgun analysis revealed a wide array of changes in individual ceramide species in DRG neurons of apoE KO mice, and the changes for ceramide species OH_N15:0 made it a candidate inhibitor of sprouting (increased in apoE KO mice and normalized by fumonisin B1). Nevertheless, the unknown effects of individual ceramide species on sprouting, as well as the variability of their changed levels in apoE KO mice and how these were affected by fumonisin B1, support a different conclusion. We suggest that absence of apoE expression alters the balance among ceramide species to one that collectively inhibits compensatory sprouting, whereas fumonisin B1 establishes a new balance that allows sprouting. Nontoxic ceramide modulators might usefully promote sprouting and circuitry repair in neurodegenerative disorders in which ceramide species are perturbed, adding to the benefits of reducing ceramideinduced neuronal apoptosis.

Cholesterol Trafficking in the Brain

“…In the presence of apoE these lipids are thought to be re-utilized. In line with this, it was reported that apoE-deficient mice display impaired compensatory sprouting in injured denervated skin (Maysinger et al 2008) .…”

The Association between Apolipoprotein E and Traumatic Brain Injury Severity and Functional Outcome in a Rehabilitation Sample

“…Research indicates that following CNS damage, ApoE plays a role in maintaining cerebral vasculature (Liaquat et al, 2002;Lynch et al, 2002;Teasdale et al, 2005), modulating the inflammatory response (Lynch et al, 2001(Lynch et al, , 2002, moderating oxidative stress, and mediating upregulation of lipid distribution to neurons for cell maintenance, growth, and repair (Aoki et al, 2003;Lynch et al, 2002;Maysinger et al, 2008;Shea et al, 2002;Strittmatter et al, 1993). Increased ApoE levels are evident in and around areas of ischemic brain damage (Aoki et al, 2003), with evidence suggesting it may reduce glutamate-induced excitotoxocity (Aono et al, 2002), and that ApoE receptors may affect regional calcium influx via NMDA receptors (Hoe et al, 2006).…”

“…ApoE is the main lipoprotein found in the brain and cerebrospinal fluid (CSF), where it appears to play a role in cell maintenance and growth (Maysinger et al, 2008), and in repair and regeneration following nerve damage by assisting with the delivery of cholesterol into damaged cells (Shea et al, 2002). ApoE is also a component of neurofibrillary tangles, binding with high-affinity to amyloid protein (Strittmatter et al, 1993).…”

The Akt-Nitric Oxide-cGMP Pathway Contributes to Nerve Growth Factor-Mediated Neurite Outgrowth in Apolipoprotein E Knockout Mice

“…However, we found no change in mRNA levels of trkA in the DRG of apoE(Ϫ/Ϫ) and wild-type mice. Another study has reported that in apoE(Ϫ/Ϫ) mice, the cutaneous NGF amount or level of trkA expression did not change in apoE(Ϫ/Ϫ) mice compared with that in wildtype mice (Maysinger et al, 2008). These results indicate that the NGF signaling pathways in apoE(Ϫ/Ϫ) mice are dysfunctional.…”