Abstract
BackgroundThe apolipoprotein E4 (apoE4) genotype is a major risk factor for developing late-onset Alzheimer’s disease (AD). Inheritance of apoE4 is also associated with impairments in olfactory function in early stages of AD. In this project we examined the effects of the three common isoforms of human apoE (apoE2, apoE3, and apoE4) on neuronal differentiation and neurite outgrowth in explant cultures of mouse olfactory epithelium (OE).ResultsThe OE cultures derived from apoE-deficient/knockout (KO) mice have significantly fewer neurons with shorter neurite outgrowth than cultures from wild-type (WT) mice. Treatment of the apoE KO culture with either purified human apoE2 or with human apoE3 significantly increased neurite outgrowth. In contrast, treatment with apoE4 did not have an effect on neurite outgrowth. The differential effects of human apoE isoforms on neurite outgrowth were abolished by blocking the low-density lipoprotein receptor-related protein (LRP) with lactoferrin and receptor-associated protein (RAP).ConclusionApoE2 and apoE3 stimulate neurite outgrowth in OE cultures by interacting with the lipoprotein receptor, LRP. ApoE4, the isoform associated with AD, failed to promote neurite outgrowth, suggesting a potential mechanism whereby apoE4 may lead to olfactory dysfunction in AD patients.
Highlights
The apolipoprotein E4 genotype is a major risk factor for developing late-onset Alzheimer’s disease (AD)
We found that (1) olfactory epithelium (OE) cultures derived from Apolipoprotein E (apoE) KO mice have significantly fewer neurons with shorter neurite outgrowth than cultures from WT mice; (2) treatment of apoE KO cultures with either purified apoE2 or apoE3 significantly increased neurite outgrowth, whereas treatment with apolipoprotein E4 (apoE4) had no effect; and (3) the differential effects of human apoE isoforms on neurite outgrowth were abolished by blocking the low-density lipoprotein receptor-related protein (LRP) with lactoferrin and receptor associated protein (RAP)
The results from this study showed that apoE plays a critical role in differentiation and neurite outgrowth in olfactory sensory neurons
Summary
The apolipoprotein E4 (apoE4) genotype is a major risk factor for developing late-onset Alzheimer’s disease (AD). Inheritance of apoE4 is associated with impairments in olfactory function in early stages of AD. In this project we examined the effects of the three common isoforms of human apoE (apoE2, apoE3, and apoE4) on neuronal differentiation and neurite outgrowth in explant cultures of mouse olfactory epithelium (OE). ApoE functions in the redistribution of lipids by binding to the low-density lipoprotein (LDL) receptor and the LDL receptor-related protein (LRP) family members [2]. The most common isoform, apoE3, contains cysteine and arginine at positions 112 and 158, respectively [3]. Mice have one form of apoE, which is similar to human apoE3 in its structural and functional properties, including receptor binding and lipoprotein preferences [3]
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