Human Apolipoprotein E Genotype Differentially Affects Olfactory Behavior and Sensory Physiology in Mice

Abstract

Apolipoprotein E (ApoE) is an important lipid carrier in both the periphery and the brain. The ApoE ε4 allele (ApoE4) is the single most important genetic risk-factor for Alzheimer's disease (AD) while the ε2 allele (ApoE2) is associated with a lower risk of AD-related neurodegeneration compared to the most common variant, ε3 (ApoE3). ApoE genotype affects a variety of neural circuits; however, the olfactory system appears to provide early biomarkers of ApoE genotype effects. Here, we directly compared olfactory behavior and olfactory system physiology across all three ApoE genotypes in 6-month- and 12-month-old mice with targeted replacement for the human ApoE2, ApoE3, or ApoE4 genes. Odor investigation and habituation were assessed, along with, olfactory bulb and piriform cortical local field potential activity. The results demonstrate that while initial odor investigation was unaffected by ApoE genotype, odor habituation was impaired in E4 relative to E2 mice, with E3 mice intermediate in function. There was also significant deterioration of odor habituation from 6 to 12 months of age regardless of the ApoE genotype. Olfactory system excitability and odor responsiveness were similarly determined by ApoE genotype, with an ApoE4 > ApoE3 > ApoE2 excitability ranking. Although motivated behavior is influenced by many processes, hyper-excitability of ApoE4 mice may contribute to impaired odor habituation, while hypo-excitability of ApoE2 mice may contribute to its protective effects. Given that these ApoE mice do not have AD pathology, our results demonstrate how ApoE affects the olfactory system at early stages, prior to the development of AD.

Apolipoprotein E regulates the maturation of injury-induced adult-born hippocampal neurons following traumatic brain injury

“…Together, these previous findings may help to explain the cognitive impairments exhibited by mice lacking ApoE or expressing ApoE4 particularly in spatial learning/memory and in olfactory memory, two neurogenic-dependent behaviors [63][64][65][66][67][68][69][70][71]. Although it remains unclear whether recovery from injuries such as TBI is dependent on neurogenesis in general and ApoE state in particular, the present study adds needed insight into a potential mechanism linking the two.…”

ApoE Regulates the Development of Adult Newborn Hippocampal Neurons

“…Hence, it is not surprising that impairments in performance in hippocampus-dependent behavioral tasks in mice deficient in ApoE or ones carrying the human ApoE4 are observed. Several studies have demonstrated that the presence of human ApoE4 or the absence of rodent ApoE impaired odor memory, Morris water maze task, and contextual fear-conditioning tasks ( Masliah et al, 1997 ; Grootendorst et al, 2001 ; Peister et al, 2006 ; Rodriguez et al, 2013 ; Salomon-Zimri et al, 2015 ; Peng et al, 2017 ; East et al, 2018 ). Further studies are required to determine the electrophysiology of newborn neurons under such genetic backgrounds to see whether they mimic the deficits in behavioral performance.…”

Exosome Production Is Key to Neuronal Endosomal Pathway Integrity in Neurodegenerative Diseases

“…Multiple mechanisms appear to drive the pathogenic effects of the APOE4 allele in the brain, including enhancing Aβ deposition while reducing Aβ clearance and degradation; modulating synaptic integrity; modulating cholesterol levels in the brain and the availability of cholesterol and other lipids to neurons; and inducing changes in reactive O 2 scavenging in the CNS Ma et al, 1994;Bales et al, 1997;Higgins et al, 1997;Haan et al, 1999;Holtzman et al, 2000;Shibata et al, 2000;Bu, 2009;Kim et al, 2009;Kolovou et al, 2009;Andrews-Zwilling et al, 2010;Verghese et al, 2011;Villemagne et al, 2011;Leung et al, 2012;Mahley and Huang, 2012;Andrews et al, 2013;Liu et al, 2013;Reinvang et al, 2013;Zlokovic, 2013;Rodriguez et al, 2014). In the absence of a dementia diagnosis, human APOE4-carriers still display structural and functional differences within regions of the hippocampus and cortex, and cognitive decline compared to age-matched non-carriers (Bookheimer and Burggren, 2009;Filippini et al, 2009;Olofsson et al, 2010;Sheline et al, 2010;Wisdom et al, 2011;Liu et al, 2013;Di Battista et al, 2016), and mouse models show cognitive deficits linked to APOE4 expression without AD pathology (Leung et al, 2012;Peng et al, 2017;East et al, 2018).…”