Impact of apoE deficiency during synaptic remodeling in the mouse olfactory bulb

Abstract

In this study we examined the role of apoE on the rate of synaptic recovery in the olfactory bulb (OB) following olfactory epithelium (OE) lesioning in mice. We used both immunoblotting and immunohistochemical techniques to compare the density of OB synaptophysin (Syn, a synaptic marker) in apoE-gene deficient/knockout (KO) mice and wild-type (WT) mice following OE lesion. We found that the whole bulb concentrations of Syn, measured by immunoblotting, declined sharply following injury in both WT and KO mice during the degenerative phase (3-7 days). After this initial decline, the Syn concentration gradually increased to normal levels by 56 days in WT mice. In contrast, Syn concentration in KO mice did not recover by day 56 when Syn density in WT was essentially normal. Glomerular Syn density, measured by immunohistochemistry, found a lower density in KO mice at all time points post lesion. This lower concentration of whole bulb Syn parallels the slower recovery of glomerular area in KO mice. The data indicate that apoE deficiency in KO mice is associated with a delayed recovery of the glomerular area and a slower recovery in Syn concentration in the OB. Keywords apoE; synaptophysin; olfactory bulb; glia; olfactory nerve; glial proteins; transgenic mice Apolipoprotein E (apoE), a lipid transporting protein, is widely expressed in the primary olfactory pathway [6,12,13,23,25]. Previous studies from our laboratories and others have shown apoE expression in the olfactory nerve and around the glomeruli in the OB of adult mice [12,23]. ApoE levels in the OB were two fold higher than normal immediately following OE lesion, and remained elevated over a 3-week period when axons from the newly differentiated olfactory receptor neurons (ORN) grew to reestablish the synaptic connections with cells in the glomeruli [13]. The precise function of apoE in the olfactory system during normal and injury-induced remodeling is unclear; however, studies suggest a role for apoE in the synaptogenesis of the CNS [2,8,20,27].

At the interface of sensory and motor dysfunctions and Alzheimer's disease

“…In mice that are genetically deficient of APOE , the rate of olfactory nerve regeneration in the OE is significantly delayed, along with multiple measures of olfactory function (66–68). Although the synaptic integrity of the OB is also compromised in the APOE deficient mice (69), it is not yet known whether its regenerative capacity is also decreased or delayed. Interestingly, estrogen treatment has been shown to stimulate the regeneration of OE and synaptogenesis of OB in an APOE -dependent manner (70).…”

Regulation of astroglia by gonadal steroid hormones under physiological and pathological conditions

“…Another factor that may mediate estradiol-induced neuroglial plasticity is apolipoprotein E (ApoE) (Struble et al, 2007), which levels have been shown to depend on gonadal steroid levels in vivo and in vitro (Stone et al, 1997;Struble et al, 2007). Although the precise mechanisms of ApoE in neuro-glial plasticity are still unknown, this molecule seems to be crucial for that function (Blain et al, 2006;Nwosu et al, 2008;White et al, 2001) and it is involved in the effects of estradiol on axonal growth in vitro (Nathan et al, 2004).…”

Acute responses to estradiol replacement in the olfactory system of apoE-deficient and wild-type mice

“…One possible explanation for this difference is that cell genesis rates in KO and WT are comparable but, as we have shown axonal growth and synaptogenesis following a lesion of the OE are delayed in KO mice (Nathan et al, 2005; Nwosu et al, 2008). Hence, increased OMP cell density in WT OE, regardless of estradiol replacement indicates that apoE facilitates maturation of OSN to phenotypically adult cells.…”

“…Overall, estradiol was associated with increased Syn but the baseline level and magnitude of increase was suppressed by the absence of apoE. A decrease in Syn staining has been shown in the hippocampus, neocortex, and OB of apoE KO mice (Masliah et al, 1995; Nwosu et al, 2008). Our data parallel these previous studies and present a possible mechanism to explain this.…”