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Expression of the Cerebral Olfactory Receptors Olfr110/111 and Olfr544 Is Altered During Aging and in Alzheimer’s Disease-Like Mice

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Abstract

A growing number of studies report the expression of olfactory receptors (ORs) in many non-chemosensory tissues and organs. However, within the brain, very few ectopic ORs are exhaustively documented. Their kinetic expression, cellular localization, and functions remain elusive. Using cDNA microarrays, quantitative PCR, and immunohistochemistry, we studied the cellular and sub-cellular localization of Olfr110/111 and Olfr544 and their timely expression in various brain areas of wild-type and transgenic Alzheimer’s disease-like (5xFAD) mice. We observed that Olfr110/111 and Olfr544 proteins are mainly expressed by neurons in cortical and hippocampal regions and, to a lesser extent, by astrocytes, microglia, oligodendrocytes, and endothelial cells. In addition, both ORs are present at the cell membrane and co-expressed with the olfactory Gαolf protein, suggesting that they can be functional. Remarkably, we also found that the expression of the mRNA encoding for Olfr110/111 tends to increase with age in both the cortex and hippocampus of wild-type and transgenic mice. Moreover, Olfr110/111 transcript expression is markedly impaired in the brain of Alzheimer’s disease-like mice. A different profile is noticed for Olfr544, for which an overexpression is observed only in the cortex of 9-month-old animals. In addition, in transgenic mice, olfactory receptors are observed near amyloid plaques. Altogether, our findings indicate that ORs may play a role in brain functioning, in normal and pathological conditions.

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Acknowledgements

We thank Kevin Baranger for providing the animals needed and for its helpful comments.

Funding

This work was supported by a research grant from the GPM (“Groupement Pasteur Mutualité”). Fanny Gaudel was a recipient of fellowships from the Edmond Roudnitska Foundation.

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Authors and Affiliations

  1. Aix Marseille Univ, CNRS, INP, Marseille, France

    Fanny Gaudel, Delphine Stephan, Véréna Landel, Gilles Sicard, François Féron & Gaëlle Guiraudie-Capraz

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  1. Fanny Gaudel
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Correspondence to Gaëlle Guiraudie-Capraz.

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François Féron and Gaëlle Guiraudie-Capraz equally supervised this work.

Electronic Supplementary Material

Supplementary Table 1

Dysregulated expression of genes coding for olfactory receptors in the cortex and hippocampus of 5xFAD mice, at M1, M4, M6 and M9. Overexpressed and under-expressed transcripts in transgenic mice are indicated in red and green, respectively. Olfr: Olfactory receptor; Gnal: Gαolf; Adcy3: Adenylyl cyclase 3. n = 3 per group (pooled results). (PNG 282 kb)

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Supplementary Figure 1

Tissue-dependent expression of mRNAs coding for Olfr110/111, Olfr544 and Gαolf protein. In comparison with the olfactory mucosa, Olfr110/111, Olfr544 and Gαolf transcripts are poorly expressed in the central nervous system. A receptor-related expression profile is observed: Olfr110/111 is more predominant in the cortex and the eye at M4, M9 and M12 (a) while Olfr544 is more abundantly expressed in the cerebellum, at M4, M9 and M12 (b) and Gαolf is less expressed in the eye than in the cortex, the hippocampus and the cerebellum, at M4, M9 and M12. n = 6 per group. **, p < 0,01 (Mann and Whitney non-parametric test). M4, 4 months; M9, 9 months; M12, 12 months; WT, wild type mice. Olfr110/111, olfactory receptors 110/111 (green); Olfr544, olfactory receptor 544 (pink); Gαolf, Gαolf protein gene (dark pink). (PNG 834 kb)

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Supplementary Figure 2

Neuronal expression of Olf110/111 and Olfr544. The cortex (a, c) and hippocampus (b, d) of M9 WT mice were double-immunostained with specific antibodies for neurons (NeuN, green) and the two studied receptors (magenta). Olfr110/111 (a, b) and Olfr544 (c, d) are weakly expressed by a small number of neurons. Scale bar = 10 μm. (PNG 7414 kb)

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Supplementary Figure 3

Expression of Olf110/111 and Olfr544 in astrocytes. The cortex (a, c) and hippocampus (b, d) of M9 WT mice were double-immunostained with specific antibodies for astrocytes (GFAP, green) and the two studied receptors (magenta). Olfr110/111 (a, b) and Olfr544 (c, d) are weakly expressed by a few astrocytes. Scale bar = 10 μm. (PNG 2747 kb)

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Supplementary Figure 4

Expression of Olfr110/111 and Olfr544 in neurons, astrocytes and microglia. Brain sections of M9 transgenic mice were double-immunostained with specific antibodies for Olfr110/111 or Olfr544 (magenta), neurons (a-d), astrocytes (e-h) and microglia (i-l). For Olfr110/111, the dilutions 1:100 (a, e, i) and 1:1000 (b, f, j) were used. For Olfr544, the dilutions 1:200 (c, g, k) and 1:1000 (d, h, l) were used. Scale bar = 10 μm. (PNG 18365 kb)

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Supplementary Figure 5

Expression of Olfr110/111 and Olfr544 in the brains of M9 5xFAD mice. Olfr110/111 (top, magenta) and Olfr544 (bottom, magenta) are observed in the vicinity of amyloid plaques (green). Scale bar = 10 μm. (PNG 3505 kb)

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Supplementary Figure 6

Olfr110/111 and Olfr544 are present at the cell membrane. Hippocampal sections of M6 WT mice were double-stained with specific antibodies for Olfr110/111 (a, b, c) and Olfr544 (d, e, f) (magenta), and a fluorescent marker of the cell membrane (WGA, Wheat Germ Agglutinin, green). Both receptors are observed at the cell membrane, in the dentate gyrus (a, d), the CA3 filed (b, e) and the cortex (c, f). Scale bar = 5 μm. (PNG 8119 kb)

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Supplementary Figure 7

Olfr110/111 and Olfr544 are co-expressed with Gαolf in the hippocampus and cortex. Hippocampal sections of M9 transgenic mice were double-stained with specific antibodies for Olfr110/111 (a, b, c), Olfr544 (d, e, f) (magenta) and Gαolf (green). Both receptors are co-expressed with Gαolf in the dentate gyrus (a, d), the CA3 filed (b, e) and the cortex (c, f). Scale bar = 10 μm. (PNG 10078 kb)

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Supplementary Figure 8

Time- and area-dependent expression of the transcripts coding for Olfr110/111 and Olfr544. In comparison with wild type animals, transgenic mice display an increased expression of Olfr110/111, at all time points, in the cortex (a) and the hippocampus (b). For Olfr544 (c, d), a dysregulated expression is observed only at M6, in the cortical area. n = 6 per group. *: p < 0,05; **: p < 0,01 (Mann and Whitney non-parametric test). M4, 4 months; M6, 6 months; M9, 9 months; M12, 12 months; Tg, 5xFAD transgenic mice (striped); WT, wild type mice (flat); Olfr110/111, olfactory receptors 110/111 (green); Olfr544, olfactory receptor 544 (pink). (PNG 538 kb)

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Supplementary Figure 9

Western-blot analysis of the heterologous expression of Olfr110 and Olfr544 in HEK293T cells. The proteins extracted from HEK cells, transfected with either Olfr110 or Olfr544 or pcDNA3.1 were submitted to an immunolabeling with antibodies raised against Olfr110 or Olfr544. The anti-Olfr110 and anti-Olfr544 antibodies reveal a protein weighing about 35 kDa. Both immunolabeled proteins are expressed in the transiently OR transfected-HEK cells but no protein is detected in pcDNA3.1 transfected-HEK cells, as expected. (PNG 540 kb)

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Gaudel, F., Stephan, D., Landel, V. et al. Expression of the Cerebral Olfactory Receptors Olfr110/111 and Olfr544 Is Altered During Aging and in Alzheimer’s Disease-Like Mice. Mol Neurobiol 56, 2057–2072 (2019). https://doi.org/10.1007/s12035-018-1196-4

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  • DOI: https://doi.org/10.1007/s12035-018-1196-4

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