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However, the precise mechanisms contributing to cholinergic dysfunction are not fully elucidated. Herein, we evaluated the cholinergic system in wild type (WT) mice and AD\u2010model (\n                    <jats:italic>App<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>NL\u2010G\u2010F<\/jats:italic>\n                    <\/jats:sup>\n                    ) mice exhibiting overproduction of amyloid\u2010beta 42 (A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    ). In superfusion experiments, [\n                    <jats:sup>3<\/jats:sup>\n                    H]acetylcholine (ACh) release from the frontal cortex and hippocampal segments preloaded with [\n                    <jats:sup>3<\/jats:sup>\n                    H]choline exhibited no significant differences between adult (6\u20138\u2009months old) and aged (12\u201317\u2009months old) WT mice. Uptake of [\n                    <jats:sup>3<\/jats:sup>\n                    H]choline via the high\u2010affinity choline transporter 1 (CHT1) and the subsequent formation\/storage of [\n                    <jats:sup>3<\/jats:sup>\n                    H]ACh showed a moderate tendency to decrease associated with aging. In contrast, in\n                    <jats:italic>App<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>NL\u2010G\u2010F<\/jats:italic>\n                    <\/jats:sup>\n                    mice, [\n                    <jats:sup>3<\/jats:sup>\n                    H]ACh release was significantly reduced in both the adult and aged groups, with reductions closely related to impaired CHT1 activity and diminished ACh synthesis\/storage at cholinergic terminals. Presynaptic cholinergic feedback mechanisms regulating ACh release, as well as the density and subtype distribution of muscarinic ACh receptors, were minimally affected by both aging and A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    overproduction. These results support the A\u03b2 hypothesis, suggesting that presynaptic cholinergic dysfunction arises early and is specifically caused by decreased CHT1 function in the AD forebrain, independent of age\u2010dependent degeneration.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70081-fig-0006-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70081","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T03:45:03Z","timestamp":1747107903000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Evaluation of the Alterations in Central Cholinergic Neurotransmission in Aging and Amyloid Precursor Protein Knock\u2010In Mice"],"prefix":"10.1111","volume":"169","author":[{"given":"Itsumi","family":"Nagai\u2010Arakawa","sequence":"first","affiliation":[{"name":"Department of Neurology Nagoya City University Graduate School of Medicine  Nagoya Aichi Japan"},{"name":"Department of Genomic Science and Microbiology Faculty of Medical Sciences, University of Fukui  Fukui Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6881-5391","authenticated-orcid":false,"given":"Ikunobu","family":"Muramatsu","sequence":"additional","affiliation":[{"name":"Department of Genomic Science and Microbiology Faculty of Medical Sciences, University of Fukui  Fukui Japan"},{"name":"Department of Pharmacology School of Medicine, Kanazawa Medical University  Uchinada Ishikawa 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University of Fukui  Fukui Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideyuki","family":"Maeda","sequence":"additional","affiliation":[{"name":"Division of Laboratory Animal Resources Life Science Support Center, University of Fukui  Fukui Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Madokoro","sequence":"additional","affiliation":[{"name":"Department of Neurology Nagoya City University Graduate School of Medicine  Nagoya Aichi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toyohiro","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Neurology Nagoya City University Graduate School of Medicine  Nagoya Aichi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuto","family":"Uchida","sequence":"additional","affiliation":[{"name":"Department of Neurology Nagoya City University Graduate School of Medicine  Nagoya Aichi 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