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Evaluation of the Relationship Between Cognitive Impairment, Glycometabolism, and Nicotinic Acetylcholine Receptor Deficits in a Mouse Model of Alzheimer’s Disease

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Abstract

Purpose

In patients with Alzheimer’s disease (AD), the loss of cerebral nicotinic acetylcholine receptors (nAChRs) that are implicated in higher brain functions has been reported. However, it is unclear if nAChR deficits occur in association with cognitive impairments. The purpose of this study was to assess the relationship between nAChR deficits and cognitive impairments in a mouse model of AD (APP/PS2 mice).

Procedures

The cognitive abilities of APP/PS2 and wild-type mice (aged 2–16 months) were evaluated using the novel object recognition test. Double-tracer autoradiography analyses with 5-[125I]iodo-A-85380 ([125I]5IA: α4β2 nAChR imaging probe) and 2-deoxy-2-[18F]fluoro-D-glucose were performed in both mice of different ages. [123I]5IA-single-photon emission tomography (SPECT) imaging was also performed in both mice at 12 months of age. Furthermore, each age cohort was investigated for changes in cognitive ability and expression levels of α7 nAChRs and N-methyl-D-aspartate receptors (NMDARs).

Results

No significant difference was found between the APP/PS2 and wild-type mice at 2–6 months of age in terms of novel object recognition memory; subsequently, however, APP/PS2 mice showed a clear cognitive deficit at 12 months of age. [125I]5IA accumulation decreased in the brains of 12-month-old APP/PS2 mice, i.e., at the age at which cognitive impairments were first observed; this result was supported by a reduction in the protein levels of α4 nAChRs using Western blotting. nAChR deficits could be noninvasively detected by [123I]5IA-SPECT in vivo. In contrast, no significant changes in glycometabolism, expression levels of α7 nAChRs, or NMDARs were associated with cognitive impairments in APP/PS2 mice.

Conclusion

A decrease in cerebral α4β2 nAChR density could act as a biomarker reflecting cognitive impairments associated with AD pathology.

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Funding

This work was supported in part by a Grant-in-Aid for COE projects by MEXT, Japan, titled “Center of excellence for molecular and gene targeting therapies with micro-dose molecular imaging modalities,” a Grant-in-Aid for Challenging Exploratory Research (KAKENHI Nos. 26670562 and 16K15583) from the Japan Society for the Promotion of Science, and a grant from the Smoking Research Foundation. Yuki Matsuura gratefully acknowledged the funding received from Nagai Memorial Research Scholarship from the Pharmaceutical Society of Japan.

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Authors and Affiliations

  1. Department of Biofunction Imaging Analysis, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima naka, Kita-ku, Okayama, 7008530, Japan

    Yuki Matsuura, Masashi Ueda, Yusuke Higaki & Shuichi Enomoto

  2. Radioisotopes Research Laboratory, Kyoto University Hospital, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 6068507, Japan

    Kohei Sano

  3. Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 6068501, Japan

    Kohei Sano & Hideo Saji

  4. Next-Generation Imaging Team, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima minami-machi, Chuo-ku, Kobe, Hyogo, 6500047, Japan

    Shuichi Enomoto

Authors
  1. Yuki Matsuura
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  2. Masashi Ueda
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  3. Yusuke Higaki
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  4. Kohei Sano
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  5. Hideo Saji
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  6. Shuichi Enomoto
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Corresponding author

Correspondence to Masashi Ueda.

Ethics declarations

Animal experiments were performed in accordance with the guidelines of the Okayama University and Kyoto University Animal Care Committees. The experimental procedures performed were approved by both care committees.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Matsuura, Y., Ueda, M., Higaki, Y. et al. Evaluation of the Relationship Between Cognitive Impairment, Glycometabolism, and Nicotinic Acetylcholine Receptor Deficits in a Mouse Model of Alzheimer’s Disease. Mol Imaging Biol 21, 519–528 (2019). https://doi.org/10.1007/s11307-018-1253-4

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  • DOI: https://doi.org/10.1007/s11307-018-1253-4

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