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Neuroscience. 2018 Jun 1;380:103-110. doi: 10.1016/j.neuroscience.2018.04.009. Epub 2018 Apr 18.

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

Author information

1
Emotional Brain Institute, Nathan S. Kline Institute, Orangeburg, NY 10962, USA; Department of Child & Adolescent Psychiatry, New York University School of Medicine, New York, NY 10016, USA. Electronic address: brett.east@nki.rfmh.org.
2
Emotional Brain Institute, Nathan S. Kline Institute, Orangeburg, NY 10962, USA.
3
Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA; Department of Neurology, New York University School of Medicine, New York, NY 10016, USA.
4
Emotional Brain Institute, Nathan S. Kline Institute, Orangeburg, NY 10962, USA; Department of Child & Adolescent Psychiatry, New York University School of Medicine, New York, NY 10016, USA; Department of Psychology, Stockholm University, SE-10691 Stockholm, Sweden.
5
Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA; Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA; Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA; The Neuroscience Institute, New York University School of Medicine, New York, NY 10016, USA.
6
Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA; Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA.
7
Emotional Brain Institute, Nathan S. Kline Institute, Orangeburg, NY 10962, USA; Department of Child & Adolescent Psychiatry, New York University School of Medicine, New York, NY 10016, USA; The Neuroscience Institute, New York University School of Medicine, New York, NY 10016, USA; Department of Neuroscience & Physiology, New York University School of Medicine, New York, NY 10016, USA.

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.

KEYWORDS:

Alzheimer’s disease; apolipoprotein E; odor habituation; olfaction; olfactory bulb; piriform cortex

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