Evaluation of the Relationship Between Cognitive Impairment, Glycometabolism, and Nicotinic Acetylcholine Receptor Deficits in a Mouse Model of Alzheimer’s Disease
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).
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).
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.
A decrease in cerebral α4β2 nAChR density could act as a biomarker reflecting cognitive impairments associated with AD pathology.
Key wordsAlzheimer’s disease Nicotinic acetylcholine receptors 2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) 5-[123I]Iodo-3-[2(S)-azetidinylmethoxy]pyridine ([123I]5IA) APP/PS2 mice
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.
Compliance with Ethical Standards
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.
- 10.Saji H, Ogawa M, Ueda M, Iida Y, Magata Y, Tominaga A, Kawashima H, Kitamura Y, Nakagawa M, Kiyono Y, Mukai T (2002) Evaluation of radioiodinated 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine as a ligand for SPECT investigations of brain nicotinic acetylcholine receptors. Ann Nucl Med 16:189–200CrossRefGoogle Scholar
- 14.Toda T, Noda Y, Ito G et al (2011) Presenilin-2 mutation causes early amyloid accumulation and memory impairment in a transgenic mouse model of Alzheimer’s disease. J Biomed Biotechnol 2011. doi: https://doi.org/10.1155/2011/617974
- 22.Richards JG, Higgins GA, Ouagazzal AM, Ozmen L, Kew JNC, Bohrmann B, Malherbe P, Brockhaus M, Loetscher H, Czech C, Huber G, Bluethmann H, Jacobsen H, Kemp JA (2003) PS2APP transgenic mice, coexpressing hPS2mut and hAPPswe, show age-related cognitive deficits associated with discrete brain amyloid deposition and inflammation. J Neurosci 23:8989–9003CrossRefGoogle Scholar