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

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.

Download Full-text

P1-283: The effect of APOE genotype on brain levels of oxysterols in young and old human APOE ∊2, ∊3 and ∊4 knock-in mice

Alzheimer s & Dementia ◽

10.1016/j.jalz.2010.05.835 ◽

2010 ◽

Vol 6 ◽

pp. S255-S256

Author(s):

Wei Ling Florence Lim ◽

Andrew M. Jenner ◽

Mary Pei Ern Ng ◽

Markus R. Wenk ◽

Guanghou Shui ◽

...

Keyword(s):

Apoe Genotype ◽

Human Apoe ◽

Brain Levels

Download Full-text

Topographic patterns of responsiveness to odorants in the rat olfactory epithelium

Journal of Neurophysiology ◽

10.1152/jn.1994.71.1.150 ◽

1994 ◽

Vol 71 (1) ◽

pp. 150-160 ◽

Cited By ~ 45

Author(s):

A. Mackay-Sim ◽

S. Kesteven

Keyword(s):

Olfactory Epithelium ◽

Nasal Septum ◽

Regional Differences ◽

Odorant Receptor ◽

Mammalian Species ◽

Topographic Maps ◽

Response Latencies ◽

Receptor Proteins ◽

Electrophysiological Recordings ◽

The Mean

1. Regional differences in odorant-induced responsiveness of the rat olfactory epithelium were measured via electrophysiological recordings [negative component of electro-olfactogram (Veog(-)) made from the surface of the olfactory epithelium on the nasal septum]. The nasal septum provided a flat surface from which multiple recordings could be made. 2. Veog(-)s were recorded from a standardized grid of 16 sites. This grid of recording sites extended over most of the surface of the olfactory epithelium on the nasal septum. 3. Twenty-one animals were tested for their responses to seven odorants. The animals were divided into three groups, each of which was tested with two different odorants plus amyl acetate, which provided a comparison between the groups. 4. For each odorant in each animal, topographic maps of relative responsiveness were derived to test whether odorants elicited different patterns of responses in the same individual. Topographic maps of responsiveness were derived also for the animal groups to test for the generality of the form of the maps for different odorants. Response latencies were also measured for each odorant at each recording site. 5. All individuals showed different topographic patterns of responses to the three test odorants. For most odorants, the location of the most responsive site was similar in all animals. In different animals the topographic maps for the same odorant were remarkably similar. Topographic maps for the odorants were all different from one another. 6. These results are consistent with the hypothesis that odorant quality is encoded in the differential spatial distribution of receptor cells whose differences in responsiveness appear to be distributed as a continuum across the epithelium. The results establish for a mammalian species what was previously reported in amphibians. These differences are presumed to be due to differential expression of odorant receptor proteins. 7. The mean response latency was 32 ms. This period was similar for all odorants, all animals, and all recording sites and was independent of Veog(-) amplitude. It is concluded that diffusion through the mucus contributed approximately 6 ms to the latency of onset of the responses to these odorants.

Download Full-text

Age-Dependent Activation and Neuronal Differentiation of Lgr5+ Basal Cells in Injured Olfactory Epithelium via Notch Signaling Pathway

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2020.602688 ◽

2020 ◽

Vol 12 ◽

Author(s):

Xuewen Li ◽

Meimei Tong ◽

Li Wang ◽

Yumei Qin ◽

Hongmeng Yu ◽

...

Keyword(s):

Notch Signaling ◽

Signaling Pathway ◽

Sensory Neurons ◽

Olfactory Epithelium ◽

Three Dimensional ◽

Notch Signaling Pathway ◽

Basal Cells ◽

Aged Mice ◽

Age Dependent ◽

Notch Activation

Aging is an important factor affecting function of smell, leading to the degeneration of mature olfactory sensory neurons and inducing the occurrence of smell loss. The mammalian olfactory epithelium (OE) can regenerate when subjected to chemical assaults. However, this capacity is not limitless. Inactivation of globose basal cells and failure to generate sensory neurons are the main obstacles to prevent the OE regeneration. Here, we found the significant attenuation in mature sensory neuronal generation and apparent transcriptional alternation in the OE from aged mice compared with young ones. The recruitment of leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)-positive cells in injured OE was weakened in aged mice, and more Lgr5+ cells remained quiescence in aged OE postinjury. Lineage-traced progenies from Lgr5+ cells were significantly fewer in the OE with aging. Moreover, Notch activation enhanced the neuronal regeneration in aged OE, making the regenerative capacity of aged OE comparable with that of young animals after injury. The growth and morphology of three-dimensional (3D)-cultured organoids from the OE of young and aged mice varied and was modulated by small molecules regulating the Notch signaling pathway. Thus, we concluded that activation of Lgr5+ cells in injured OE was age dependent and Notch activation could enhance the capacity of neuronal generation from Lgr5+ cells in aged OE after injury.

Download Full-text

Age-dependent emergence of neurophysiological and behavioral abnormalities in progranulin-deficient mice

Alzheimer s Research & Therapy ◽

10.1186/s13195-019-0540-x ◽

2019 ◽

Vol 11 (1) ◽

Author(s):

Dávid Nagy ◽

Lauren Herl Martens ◽

Liza Leventhal ◽

Angela Chen ◽

Craig Kelley ◽

...

Keyword(s):

Frontotemporal Dementia ◽

Neurodegenerative Disorder ◽

Neuronal Loss ◽

Loss Of Function ◽

Behavioral Alterations ◽

Response Latencies ◽

Reward Seeking ◽

Behavioral Abnormalities ◽

Age Dependent

Abstract Background Loss-of-function mutations in the progranulin gene cause frontotemporal dementia, a genetic, heterogeneous neurodegenerative disorder. Progranulin deficiency leads to extensive neuronal loss in the frontal and temporal lobes, altered synaptic connectivity, and behavioral alterations. Methods The chronological emergence of neurophysiological and behavioral phenotypes of Grn heterozygous and homozygous mice in the dorsomedial thalamic—medial prefrontal cortical pathway were evaluated by in vivo electrophysiology and reward-seeking/processing behavior, tested between ages 3 and 12.5 months. Results Electrophysiological recordings identified a clear age-dependent deficit in the thalamocortical circuit. Both heterozygous and homozygous mice exhibited impaired input-output relationships and paired-pulse depression, but evoked response latencies were only prolonged in heterozygotes. Furthermore, we demonstrate firstly an abnormal reward-seeking/processing behavior in the homozygous mice which correlates with previously reported neuroinflammation. Conclusion Our findings indicate that murine progranulin deficiency causes age-dependent neurophysiological and behavioral abnormalities thereby indicating their validity in modeling aspects of human frontotemporal dementia.

Download Full-text

Expression of odorant receptor genes in the catfish olfactory epithelium

Chemical Senses ◽

10.1093/chemse/18.2.209 ◽

1993 ◽

Vol 18 (2) ◽

pp. 209-216 ◽

Cited By ~ 12

Author(s):

John Ngai ◽

Andrew Chess ◽

Michael M. Dowling ◽

Richard Axel

Keyword(s):

Olfactory Epithelium ◽

Odorant Receptor

Download Full-text

Innate immune signaling in the olfactory epithelium reduces odorant receptor levels: modeling transient smell loss in COVID-19 patients

10.1101/2020.06.14.20131128 ◽

2020 ◽

Cited By ~ 3

Author(s):

Steve Rodriguez ◽

Luxiang Cao ◽

Gregory T. Rickenbacher ◽

Eric G. Benz ◽

Colin Magdamo ◽

...

Keyword(s):

Olfactory Epithelium ◽

Odorant Receptor ◽

Recovery Phase ◽

Odor Discrimination ◽

Olfactory Function ◽

Receptor Expression ◽

Odorant Receptors ◽

Type I ◽

Innate Immune Signaling ◽

Leading Symptom

Post-infectious anosmias typically follow death of olfactory sensory neurons (OSNs) with a months-long recovery phase associated with parosmias. While profound anosmia is the leading symptom associated with COVID-19 infection, many patients regain olfactory function within days to weeks without distortions. Here, we demonstrate that sterile induction of anti-viral type I interferon signaling in the mouse olfactory epithelium is associated with diminished odor discrimination and reduced odor-evoked local field potentials. RNA levels of all class I, class II, and TAAR odorant receptors are markedly reduced in OSNs in a non-cell autonomous manner. We find that people infected with COVID-19 rate odors with lower intensities and have odor discrimination deficits relative to people that tested negative for COVID-19. Taken together, we propose that inflammatory-mediated loss of odorant receptor expression with preserved circuit integrity accounts for the profound anosmia and rapid recovery of olfactory function without parosmias caused by COVID-19.

Download Full-text

Developmental changes in glucose transport, lipid composition, and fluidity of jejunal BBM

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.273.3.r1086 ◽

1997 ◽

Vol 273 (3) ◽

pp. R1086-R1093 ◽

Cited By ~ 6

Author(s):

C. M. Vazquez ◽

N. Rovira ◽

V. Ruiz-Gutierrez ◽

J. M. Planas

Keyword(s):

Glucose Uptake ◽

Glucose Transport ◽

Lipid Composition ◽

Brush Border Membrane ◽

Glucose Transporter ◽

Specific Binding ◽

Molar Ratio ◽

Site Density ◽

Age Related ◽

Age Dependent

Na(+)-dependent D-glucose uptake was studied in jejunal brush-border membrane (BBM) vesicles of chickens at 2 days and 1, 2, 5-6, and 12-14 wk of age. Both initial rates and accumulation ratios of the Na(+)-dependent D-glucose transport were significantly higher during the 1st wk than at other ages. To explain the age-related changes observed in the transport of D-glucose, the phlorizin-specific binding, Na+ permeability, lipid composition, and fluidity were studied. Transporter site density was quantified using 50 mumol/l phlorizin and found to be higher during the 1st wk. During the 2nd wk it decreased and then remained constant. Permeability of Na+, studied using 22Na+, showed that fluxes were similar during the first 6 wk, and a significant decrease was observed in the oldest group. Furthermore, membrane fluidity results showed a significant age-dependent decrease that correlated well with both the increased molar ratio of cholesterol to phospholipid and the decreased ratio of lipid to protein found during development. In conclusion, changes in the density of Na(+)-dependent D-glucose transporter as well as in lipid content and fluidity might be involved in the changes observed in D-glucose uptake during the posthatching development.

Download Full-text