Elevated Flotillin-1 in Saliva and Salivary Glands: A Novel Non-Invasive Biomarker in an Alzheimer’s Disease Mouse Model

<b>Background/Objectives:</b> Alzheimer's disease (AD) is currently diagnosed using established biomarkers, such as reduced cerebrospinal fluid (CSF) Aβ₄₂, 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. <b>Methods:</b> Wild-type (WT) and <i>App^NL-G-F</i> (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 Aβ₄₂ levels were analyzed using Western blotting and ELISA, respectively. <b>Results:</b> 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 Aβ₄₂ levels were markedly increased only in the 9-month-old APP-KI group. <b>Conclusions:</b> Flotillin-1 levels in saliva and salivary glands were significantly elevated in the presence of AD pathology. Aβ 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's disease.