Regular articleThe mechanisms underlying olfactory deficits in apolipoprotein E–deficient mice: focus on olfactory epithelium and olfactory bulb
Introduction
Alzheimer's disease (AD) is a progressive neurodegenerative disease wherein patients suffer from sensory, motor, progressive memory loss, and cognitive decline, which accounts for 60%–70% of all cases of dementia (Daulatzai, 2010). AD patients often have neuropathological changes in components of the brain involved in olfactory processing, along with a reduced ability to detect, discriminate, and identify odors (Ferrer et al., 2016, Murphy, 1999). In fact, olfactory dysfunction often precedes other clinical symptoms in chronic neurodegenerative diseases (Djordjevic et al., 2008, Zhang, 2016) and has a relatively high prevalence in various types of dementia, occurring in up to 100% of AD patients (Duff et al., 2002). In combination with neuropsychological measures, olfactory sensory dysfunction thus represents a potential clinical marker of AD severity and progression (Devanand et al., 2015, Wilson et al., 2009, Zou et al., 2016) and could be used for early diagnosis (Wesson et al., 2010).
Apolipoprotein E (ApoE) is a 35 kDa lipid transport protein expressed in various organs, including the brain, where it is especially enriched in the primary olfactory pathway (Mahley, 1988, Nathan et al., 2007). ApoE polymorphic alleles are the main genetic determinants of AD (Liu et al., 2013, Sun et al., 2016). Previous studies have shown ApoE expression in the olfactory nerve, around the glomeruli of the olfactory bulb (OB) (Nathan et al., 2001, Struble et al., 1999) and in the olfactory epithelium (OE) (Nathan et al., 2007). ApoE deficiency (ApoE−/−) leads to significantly delayed recovery, after OE injury, of mature olfactory marker protein positive (OMP+) cells in the OE (Nathan et al., 2010). It also results in delayed olfactory nerve regeneration, along with slow recovery of synaptophysin concentration in the glomerular area of the OB (Nwosu et al., 2008), indicating a vital role of ApoE in nerve repair and remodeling. In addition, ApoE−/− mice performed poorly in olfactory tests (Nathan et al., 2004), suggesting a requirement for ApoE in olfaction. However, the influence of ApoE deletion on olfaction under normal physiological conditions and the mechanisms underlying ApoE regulation of olfaction remain unclear.
In the present study, we evaluated the physiological function of ApoE in the olfactory system by detecting olfactory sensitivity in standard olfactory behavior tests in wild type (WT) and ApoE−/− mice, using a combination of electrophysiological and biochemical techniques. We addressed the following questions: when do olfactory behavioral deficits occur in ApoE−/− mice; and do corresponding early defects occur in the OE, the OB, or both? What molecular and cellular processes lead to olfactory deficits in the absence of ApoE? In addition to uncovering the timing of olfactory behavioral defects in ApoE-deficient mice, the present study reveals new aspects of ApoE involvement in odorant sensation and procession.
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Animals and genotyping
ApoE knockout mice (B6.129P2-ApoEtm1Unc/J) on the C57BL/6J background were originally obtained from the Model Animal Research Center of Nanjing University and crossed with C57BL/6J mice to get heterozygous ApoE mice (ApoE+/−). ApoE−/− and WT littermates were generated by intercrossing ApoE+/− males and females as described previously (Zhang et al., 1992). All animals were maintained in a constant temperature (23 ± 1 °C), controlled environment in individual cages with free access to food and
Cookie-finding test reveals impaired olfactory behavior in 3–5 month-old ApoE−/− mice
To investigate when olfactory deficiency caused by the absence of ApoE genes develops, we performed a cookie-finding test (see Fig. 1A), which assesses odorant perception, on 1–2 month- and 3–5 month-old ApoE−/− and WT mice. In this test, the cookie was randomly placed at the end of 1 arm of an 8-arm maze and its position changed for each trial to ensure the animal could not find it using spatial cues. We found that ApoE deficiency resulted in olfactory sensitivity deficiency in 3–5 month-old
Discussion
Despite the involvement of the ε4 ApoE allele in AD pathogenesis (Liu et al., 2013), ApoE induction is beneficial for AD treatment since ApoE inducers restore cognitive abilities in beta-amyloid mouse models (Fitz et al., 2013, Poirier et al., 2014). In this study, in addition to identifying marked differences between 1–2 month- and 3–5 month-old ApoE−/− mice, we used electrophysiological techniques to reveal that the development of olfactory behavioral impairment in ApoE−/− mice corresponds to
Disclosure statement
The authors have no conflicts of interest to disclose.
Acknowledgements
The authors would like to thank Ming Chen for suggestions on the manuscript and Xingzhi Zheng for technical support. This work was supported by grants from the National Natural Science Foundation of China (31771219), the Science and Technology Division of Guangdong Province (2013KJCX0054), the Natural Science Foundation of Guangdong Province (2014A030313418, 2014A030313440), and Guangzhou Science and Technology Bureau (201607010320).
References (65)
- et al.
Olfaction in patients with mild cognitive impairment and Alzheimer's disease
Neurobiol. Aging
(2008) Interneuron Diversity series: rhythm and mood in perisomatic inhibition
Trends Neurosci.
(2003)- et al.
Properties of external plexiform layer interneurons in mouse olfactory bulb slices
Neuroscience
(2005) - et al.
Involvement of glutamatergic and GABAergic transmission in MK-801-increased gamma band oscillation power in rat cortical electroencephalograms
Neuroscience
(2014) - et al.
Olfactory oscillations: the what, how and what for
Trends Neurosci.
(2009) - et al.
How to use the optical fractionator: an example based on the estimation of neurons in the hippocampal CA1 and CA3 regions of tree shrews
Brain Res. Brain Res. Protoc.
(2001) - et al.
GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 knockin mice
Cell Stem Cell
(2009) - et al.
Odor processing by adult-born neurons
Neuron
(2014) - et al.
Loss of CNGB1 protein leads to olfactory dysfunction and subciliary cyclic nucleotide-gated channel trapping
J. Biol. Chem.
(2006) Loss of olfactory function in dementing disease
Physiol. Behav.
(1999)
Reconstitution of the olfactory epithelium following injury in apoE-deficient mice
Exp. Neurol.
The distribution of apolipoprotein E in mouse olfactory epithelium
Brain Res.
Apolipoprotein E is upregulated in olfactory bulb glia following peripheral receptor lesion in mice
Exp. Neurol.
Olfactory function in apoE knockout mice
Behav. Brain Res.
Impact of apoE deficiency during synaptic remodeling in the mouse olfactory bulb
Neurosci. Lett.
Apolipoprotein E and lipid homeostasis in the etiology and treatment of sporadic Alzheimer's disease
Neurobiol. Aging
Synchronization of olfactory bulb mitral cells by precisely timed inhibitory inputs
Neuron
Apolipoprotein E immunoreactivity in human and mouse olfactory bulb
Neurosci. Lett.
APOE epsilon4 carriers may undergo synaptic damage conferring risk of Alzheimer's disease
Alzheimers Dement.
Adult neurogenesis and the olfactory system
Prog. Neurobiol.
Interneuron diversity series: inhibitory interneurons and network oscillations in vitro
Trends Neurosci.
Astrocytes control the development of the migration-promoting vasculature scaffold in the postnatal brain via VEGF signaling
J. Neurosci.
Interneurons produced in adulthood are required for the normal functioning of the olfactory bulb network and for the execution of selected olfactory behaviors
J. Neurosci.
Rapid and continuous activity-dependent plasticity of olfactory sensory input
Nat. Commun.
APP modulates KCC2 expression and function in hippocampal GABAergic inhibition
Elife
In vivo olfactory model of APP-induced neurodegeneration reveals a reversible cell-autonomous function
J. Neurosci.
Anesthetic regimes modulate the temporal dynamics of local field potential in the mouse olfactory bulb
J. Neurophysiol.
Tufted cell dendrodendritic inhibition in the olfactory bulb is dependent on NMDA receptor activity
J. Neurophysiol.
Parvalbumin-containing interneurons do not innervate granule cells in the olfactory bulb
Neuroreport
Analyzing responses of mouse olfactory sensory neurons using the air-phase electroolfactogram recording
J. Vis. Exp
The nature and duration of adaptation following long-term odor exposure
Percept. Psychophys.
Early stages of pathogenesis in memory impairment during normal senescence and Alzheimer's disease
J. Alzheimers Dis.
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These authors contributed equally.