{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T12:44:16Z","timestamp":1766580256006,"version":"3.48.0"},"reference-count":26,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T00:00:00Z","timestamp":1766534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant-in-Aids for Scientific Research","award":["C25K13134"],"award-info":[{"award-number":["C25K13134"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background\/Objectives: Alzheimer\u2019s disease (AD) is currently diagnosed using established biomarkers, such as reduced cerebrospinal fluid (CSF) A\u03b242, increased phosphorylated tau, and cerebral amyloid levels detected by PiB-PET. Because these methods are invasive or require specialized facilities, less invasive and easily detectable biomarkers are needed. Flotillin-1 concentrations are reduced in the CSF and serum of patients with AD. This study examined whether flotillin-1 in saliva, a less invasive specimen than blood, could serve as a biomarker. Methods: Wild-type (WT) and AppNL\u2013G\u2013F (APP knock-in; APP-KI) mice were used to create four groups (2 and 9 months of age, six animals per group). Saliva and salivary glands were collected, and flotillin-1 levels were measured using Western blotting. Intracellular signaling pathways regulating flotillin-1 and salivary gland A\u03b242 levels were analyzed using Western blotting and ELISA, respectively. Results: Flotillin-1 levels in the saliva and salivary glands were significantly higher in the 9-month-old APP-KI group than in all other groups, including age-matched WT mice. Phosphorylated extracellular signal-regulated kinase (p-ERK) levels were also significantly elevated in the 9-month-old APP-KI group, whereas phosphorylated c-Jun N-terminal kinase (p-JNK) levels did not differ significantly. Salivary gland A\u03b242 levels were markedly increased only in the 9-month-old APP-KI group. Conclusions: Flotillin-1 levels in saliva and salivary glands were significantly elevated in the presence of AD pathology. A\u03b2 accumulation in the salivary glands likely activates the ERK signaling cascade, promoting flotillin-1 expression and secretion. Thus, salivary flotillin-1 may serve as a promising noninvasive biomarker for the early diagnosis of Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.3390\/diagnostics16010061","type":"journal-article","created":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T12:22:27Z","timestamp":1766578947000},"page":"61","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Elevated Flotillin-1 in Saliva and Salivary Glands: A Novel Non-Invasive Biomarker in an Alzheimer\u2019s Disease Mouse Model"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0231-0419","authenticated-orcid":false,"given":"Sunao","family":"Kawakami","sequence":"first","affiliation":[{"name":"Periodontology, The Nippon Dental University Graduate School of Life Dentistry at Niigata, Niigata 951-8580, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0225-0658","authenticated-orcid":false,"given":"Cha-Gyun","family":"Jung","sequence":"additional","affiliation":[{"name":"Center for Nursing International Promotion, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rieko","family":"Inoue","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8222-9225","authenticated-orcid":false,"given":"Tomohisa","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Oral and Maxillofacial Surgery, Nagoya City University East Medical Center, 1-2-23 Wakamizu, Chikusa-ku, Nagoya 464-8547, Japan"},{"name":"Department of Maxillofacial Surgery, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soh","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Periodontology, The Nippon Dental University School of Life Dentistry at Niigata, 1-8 Hamaura-cho, Chuo-ku, Niigata 951-8580, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makoto","family":"Michikawa","sequence":"additional","affiliation":[{"name":"Department of Neurophysiology and Brain Science, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,24]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2019). 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