口腔-脑轴：连接三叉神经感觉运动功能障碍、慢性应激、神经炎症与神经退行性变的统一框架

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中文摘要

阿尔茨海默病（AD）和帕金森病（PD）等神经退行性疾病历经数十年发展，但其最早的致病驱动因素仍知之甚少。流行病学和实验动物研究表明，口腔感觉运动调节的紊乱，尤其是三叉神经本体感觉通路内的紊乱，可能在临床症状出现之前很久就导致神经功能障碍。中脑三叉神经核（MesV）是唯一完全位于中枢神经系统（CNS）内的初级感觉神经元群体，它将口腔本体感觉与脑干和前脑网络连接起来。慢性咬合不匹配、咀嚼受损、睡眠磨牙症和睡眠呼吸障碍可能产生持续的感觉运动预测误差，从而破坏以MesV为中心的回路稳定性，并随后招募蓝斑（LC）——大脑主要的去甲肾上腺素能应激核团。本综述提出一个口腔-脑轴模型，其中慢性MesV相关预测误差信号激活LC依赖性应激系统，导致神经免疫激活、蓝斑-天冬酰胺内肽酶（LC-AEP）通路参与以及下游蛋白质病变过程。持续的LC活动可能促进小胶质细胞启动、反应性星形胶质细胞增生和神经炎症信号传导，创造有利于LC-AEP通路激活和下游tau蛋白病理的条件。流行病学研究将牙齿缺失、咬合支持减少和咀嚼受损与痴呆风险增加联系起来，而前驱期PD的实验模型显示，在运动症状出现之前就存在早期三叉神经感觉处理异常。总之，这些发现支持以下假设：口腔感觉运动稳态的慢性紊乱可能增加神经退行性变的易感性。该框架确定了潜在的生物标志物和预防靶点，提示调节口腔功能和神经免疫通路可能有助于在不可逆的神经元丢失发生之前降低神经退行性变风险。

英文摘要

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.