Human APOE ɛ3 and APOE ɛ4 Alleles Have Differential Effects on Mouse Olfactory Epithelium

Article type: Research Article

Authors: Khan, Naazneen^a | Alimova, Yelena^a | Clark, Sophie J.^a | Vekaria, Hemendra J.^{b; c} | Walsh, Adeline E.^a | Williams, Holden C.^{a; f} | Hawk, Gregory S.^e | Sullivan, Patrick G.^{b; c; d} | Johnson, Lance A.^{a; f} | McClintock, Timothy S.^{a; *}

Affiliations: [a] Department of Physiology, University of Kentucky, Lexington, KY, USA | [b] Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, USA | [c] Department of Neuroscience, University of Kentucky, Lexington, KY, USA | [d] Lexington Veterans’ Affairs Healthcare System, Lexington, KY, USA | [e] Department of Statistics, University of Kentucky, Lexington, KY, USA | [f] Sanders Brown Center on Aging, University of Kentucky, Lexington, KY, USA

Correspondence: [*] Correspondence to: Timothy S. McClintock, Department of Physiology, University of Kentucky, Lexington, KY 40536-0298, USA. Tel.: +1 859 323 1083; E-mail: [email protected].

Abstract: Background:Alzheimer’s disease (AD) is a progressive age-dependent disorder whose risk is affected by genetic factors. Better models for investigating early effects of risk factors such as apolipoprotein E (APOE) genotype are needed. Objective:To determine whether APOE genotype produces neuropathologies in an AD-susceptible neural system, we compared effects of human APOE ɛ3 (E3) and APOE ɛ4 (E4) alleles on the mouse olfactory epithelium. Methods:RNA-Seq using the STAR aligner and DESeq2, immunohistochemistry for activated caspase-3 and phosphorylated histone H3, glucose uptake after oral gavage of 2-[1,2-3H (N)]-deoxy-D-glucose, and Seahorse Mito Stress tests on dissociated olfactory mucosal cells. Results:E3 and E4 olfactory mucosae show 121 differentially abundant mRNAs at age 6 months. These do not indicate differences in cell type proportions, but effects on 17 odorant receptor mRNAs suggest small differences in tissue development. Ten oxidoreductases mRNAs important for cellular metabolism and mitochondria are less abundant in E4 olfactory mucosae but this does not translate into differences in cellular respiration. E4 olfactory mucosae show lower glucose uptake, characteristic of AD susceptibility and consistent with greater expression of the glucose-sensitive gene, Asns. Olfactory sensory neuron apoptosis is unaffected at age 6 months but is greater in E4 mice at 10 months. Conclusion:Effects of human APOE alleles on mouse olfactory epithelium phenotype are apparent in early adulthood, and neuronal loss begins to increase by middle age (10 months). The olfactory epithelium is an appropriate model for the ability of human APOE alleles to modulate age-dependent effects associated with the progression of AD.

Keywords: Alzheimer’s disease, apoptosis, glucose metabolic disorder, mitochondria, odorant receptors, olfaction, oxidoreductases

DOI: 10.3233/JAD-215152

Journal: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1481-1494, 2022