The Oral-Brain Axis: A Unified Framework Linking Trigeminal Sensorimotor Dysfunction, Chronic Stress, Neuroinflammation, and Neurodegeneration.

Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) develop over decades, yet their earliest pathogenic drivers remain poorly understood. Epidemiological and experimental animal studies suggest that disturbances in oral sensorimotor regulation, particularly within trigeminal proprioceptive pathways, may contribute to neural dysfunction long before clinical symptoms emerge. The mesencephalic trigeminal nucleus (MesV), the only primary sensory neuron population located entirely within the central nervous system (CNS), links oral proprioception with brainstem and forebrain networks. Chronic occlusal mismatch, impaired mastication, sleep bruxism, and sleep-disordered breathing may generate persistent sensorimotor prediction errors that destabilize MesV-centered circuits and subsequently recruit the locus coeruleus (LC), the brain's principal noradrenergic stress nucleus. This review proposes an oral-brain axis model in which chronic MesV-related prediction error signaling engages LC-dependent stress systems, leading to neuroimmune activation, locus coeruleus-asparagine endopeptidase (LC-AEP) pathway engagement, and downstream proteinopathic processes. Sustained LC activity may facilitate microglial priming, reactive astrocytosis, and neuroinflammatory signaling, creating conditions that favor LC-AEP pathway activation and downstream tau pathology. Epidemiological studies associate tooth loss, reduced occlusal support, and impaired mastication with increased dementia risk, while experimental models of prodromal PD demonstrate early trigeminal sensory-processing abnormalities preceding motor symptoms. Together, these findings support the hypothesis that chronic disturbances in oral sensorimotor homeostasis may increase neurodegenerative vulnerability. This framework identifies potential biomarkers and preventive targets, suggesting that modulation of oral function and neuroimmune pathways may help reduce neurodegenerative risk before irreversible neuronal loss occurs.