Apolipoprotein E4 causes early olfactory network abnormalities and short-term olfactory memory impairments
Introduction
The human APOE gene exists as three alleles – ε2, ε3, and ε4 – which have a worldwide prevalence of 10%, 70%, and 20% respectively (Mahley et al., 2006). Compared to the more common apolipoprotein ε3 allele (ApoE3), the apolipoprotein ε4 allele (ApoE4) is strongly associated with several adverse clinical outcomes, including cardiovascular disease and Alzheimer’s disease (AD) (Farrer, 1997, Mahley et al., 2006, Mahley, 2016). Additionally, ApoE4 has been shown to influence cognitive deficits that arise prior to detectable AD pathology and in healthy older adults (Small et al., 2004, Caselli et al., 2009, Wisdom et al., 2011), suggesting that ApoE4 expression adversely impacts brain pathways independently of AD pathology. In fact, a growing body of neuroimaging research has reported functional differences in human ApoE4 carriers versus noncarriers prior to the onset of cognitive decline within diverse brain regions (such as in hippocampi and specific regions of cortex) (Small et al., 2000, Reiman et al., 2004, Bookheimer and Burggren, 2009, Filippini et al., 2009, Dennis et al., 2010, Sheline et al., 2010, Brown et al., 2011). However, ApoE4-driven functional differences within regions that might specifically explain olfactory dysfunction have largely been ignored.
Prior to broad cognitive decline, human ApoE4 carriers exhibit odor identification impairments (Graves et al., 1999, Murphy, 1999, Wilson et al., 2007, Schubert et al., 2008, Olofsson et al., 2016) that may precede later cognitive deficits (Graves et al., 1999, Wilson et al., 2007, Schubert et al., 2008). Normal olfactory activity relies on proper functioning within the olfactory network, the neural mechanisms of which are increasingly well established (Wilson, 2009): central odor processing initiates within the olfactory bulb (OB), which then transmits information directly to the piriform cortex (PCX), a region that is crucial for procedures involved in odor habituation and olfactory learning (Barnes et al., 2008, Wilson and Linster, 2008, Wilson, 2009, Gottfried, 2010). Olfactory information ultimately enters the entorhinal cortex and finally the hippocampus – a site of memory storage and retrieval (Staubli et al., 1984, Sosulski et al., 2011, Kay, 2014). Olfactory event-related potential (OERP) recordings during olfactory memory tasks in humans have demonstrated differences in peak latencies and amplitudes that distinguish ApoE4 carriers from non-carriers (Corby et al., 2012, Green et al., 2013). However, interpreting the relationship between brain activity and OERP signals measured on the scalp remains challenging (He et al., 2011). Electrode recordings of local field potentials (LFPs) in animal models allow more direct assessment of local activity in circuits directly involved in specific behaviors (Buzsaki et al., 2012). Additionally, odor-evoked LFP oscillations of the rodent olfactory system in the frequencies of 15–40 Hz (beta band; reflects long-range communication) and 40–80 Hz (gamma band; may reflect more local processing) have been shown to be especially indicative of behaviorally relevant odor processing (Neville and Haberly, 2003, Wesson et al., 2011, Kay, 2014, Martin and Ravel, 2014, Sadrian et al., 2014) and are sensitive to neuropathology related to aging (Wesson et al., 2011, Xu et al., 2015). Using LFP recordings from mice that express human ApoE, we have demonstrated within distinct olfactory regions that both ApoE4 genotype and aging play a factor in influencing the signal-to-noise ratio of an odor-evoked response, which may contribute to olfactory memory impairment.
Section snippets
Study approval
All experimental procedures involving animals in this study were approved by and complied with the guidelines of the Institutional Animal Care and Use Committee of the Nathan Kline Institute.
Mice
The mice in this study were purchased from Taconic farms (Germantown, NY, USA) and were homozygous for ApoE4 and ApoE3 on a C57BL/6 background. These targeted-replacement mice were developed to express human ApoE under the control of the endogenous murine promoter (Sullivan et al., 1997), which allows for
Behavioral olfactory deficits in young ApoE4 mice
ApoE mice were initially evaluated using a simple olfactory habituation task. As we have previously described (Wilson, 2009, Wesson et al., 2011), the length of time that a mouse spends investigating novel odors decreases with repeated presentation when olfaction is intact. Analysis of the results by trial (Fig. 1A) with a repeated measures ANOVA (trial × group) on all four groups (6 mo ApoE3, 6 mo ApoE4, 12 mo ApoE3, and 12 mo ApoE4) found a main effect of both trial (F (3,276) = 637.6, p < 0.0001)
Discussion
While previous work has demonstrated impaired olfactory guided behavior in ApoE knock-out mice (Nathan et al., 2004), the present results are the first to investigate specific ApoE genotype effects on olfactory behavior and physiology in vivo. Young (6 mo) ApoE4 compared to age-matched ApoE3 mice display both impaired behavioral odor habituation and OB hyperactivity during odor stimulation, suggesting a relationship between olfactory dysfunction onset and early stage sensory network
Funding
This work was supported by the NIA (P01-AG017617 to PMM and EL; and R01-AG037693 to DAW and EL). Katherine Peng was additionally supported by a training program (T32-GM066704, Dr. Erika Bach) and the Sackler Institute of Graduate Biomedical Sciences, New York University School of Medicine. The funding sources were not involved in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
Acknowledgments
We thank Dr. Monika Pawlik for her expert assistance with our mouse colonies. KYP did the experimentation and initial data analysis. All authors contributed to the experimental design and to the manuscript.
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