TY - JOUR
T1 - Evaluation of the Relationship Between Cognitive Impairment, Glycometabolism, and Nicotinic Acetylcholine Receptor Deficits in a Mouse Model of Alzheimer’s Disease
AU - Matsuura, Yuki
AU - Ueda, Masashi
AU - Higaki, Yusuke
AU - Sano, Kohei
AU - Saji, Hideo
AU - Enomoto, Shuichi
N1 - Funding Information:
Funding Information This work was supported in part by a Grant-in-Aid for COE projects by MEXT, Japan, titled BCenter 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.
Publisher Copyright:
© 2018, World Molecular Imaging Society.
PY - 2019/6/17
Y1 - 2019/6/17
N2 - 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.
AB - 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.
KW - 2-Deoxy-2-[F]fluoro-D-glucose ([F]FDG)
KW - 5-[I]Iodo-3-[2(S)-azetidinylmethoxy]pyridine ([I]5IA)
KW - APP/PS2 mice
KW - Alzheimer’s disease
KW - Nicotinic acetylcholine receptors
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U2 - 10.1007/s11307-018-1253-4
DO - 10.1007/s11307-018-1253-4
M3 - Article
C2 - 30047036
AN - SCOPUS:85050652585
SN - 1536-1632
VL - 21
SP - 519
EP - 528
JO - Molecular Imaging and Biology
JF - Molecular Imaging and Biology
IS - 3
ER -
