Oral Cavity and Brain Cross-talk in Alzheimer's Disease

阿尔茨海默病中的口腔和大脑交互作用

• 批准号: 10231824
• 负责人: Colin K Combs
• 金额: $ 123.01万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231824
• 关键词: AD transgenic mice; Affect; Age; Age-Months; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloidosis; Bacteria; Blood; Brain; Characteristics; Colon; Complex; Data; Dental Enamel; Dependence; Diffuse; Disease; Disease Progression; Exhibits; Feces; Female; Fluorides; Functional disorder; Gastrointestinal tract structure; Gliosis; Health; Human; Intestinal Mucosa; Mediating; Memory; Monitor; Mus; Nature; Neurodegenerative Disorders; Oral; Oral cavity; Oral health; Patients; Peptides; Performance; Periodontal Diseases; Peripheral; Population; Process; Property; Reporting; Risk; Rodent; Role; Saliva; Salivary; Salivary Glands; Sampling; Severities; Swab; Testing; Thick; Thinness; Tooth Loss; Transgenic Mice; Weaning; Wild Type Mouse; Work; amyloid precursor protein processing; base; beta secretase; brain behavior; cytokine; dementia risk; dysbiosis; fecal microbiome; gastrointestinal; gut-brain axis; human disease; immunoreactivity; inhibitor/antagonist; innovation; male; microbial; microbiome; mouse model; novel; oral bacteria; oral microbiome; prevent; saliva secretion; tau-1; transcriptome sequencing

Summary Although Alzheimer’s disease (AD) is an age-associated neurodegenerative disease, continuing evidence demonstrates pathophysiology outside of the brain. This suggests a more complex process of disease with systemic manifestations as well. Numerous studies now demonstrate that changes in the oral cavity have a relationship with AD. Human patients have elevated salivary Aβ concentrations and reported problems with saliva flow. In addition, periodontal disease, tooth loss, and overall poor oral health are all positive risk factors for AD. This suggests that AD and periodontal health may have a reciprocal relationship. Using two different transgenic mouse amyloidosis models of AD, APP/PS1 and AppNL-G-F mice, we verified not only Aβ secretion in saliva, but a unique disease-associated oral microbiome and enamel thinning and increased cavities compared to wild type controls. Based upon these findings and prior work by others, we hypothesize that that oral cavity changes are a peripheral manifestation of AD contributing to disease progression. We will continue using the AppNL-G-F mouse line to fully define oral health across age and disease stage in the first aim. In the second aim we will determine whether salivary secretion of Aβ is needed for the oral dysbiosis and decline in oral health in the AD line. In the third aim we will determine whether the oral dysbiosis is specifically responsible for the decline in oral health and brain presentation of disease in the mice. This study will define an innovative mechanism demonstrating that oral cavity dysbiosis and dysfunction is a characteristic of disease which also contributes to AD progression. We expect to find that salivary Aβ secretion contributes to oral dysbiosis and changing the oral microbiome is sufficient to ameliorate disease presentation in the brain. This will demonstrate a new bi-directional understanding of disease involving a mouth-brain axis.

总结 虽然阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，但持续的证据表明， 展示了大脑外的病理生理学这表明一个更复杂的疾病过程， 也有系统性的表现。现在许多研究表明，口腔的变化有一个 与AD的关系人类患者的唾液Aβ浓度升高，并报告了 唾液流。此外，牙周病、牙齿脱落和整体口腔健康状况不佳都是积极的风险因素 对于AD。这表明AD和牙周健康可能存在相互关系。使用两种不同 在AD、APP/PS1和AppNL-G-F小鼠的转基因小鼠淀粉样变性模型中，我们不仅证实了 唾液，但一个独特的疾病相关的口腔微生物组和牙釉质变薄和增加蛀牙相比， 野生型对照。基于这些发现和其他人先前的工作，我们假设口腔 这些变化是AD的外周表现，有助于疾病进展。我们将继续使用 AppNL-G-F小鼠系的第一个目标是全面定义跨年龄和疾病阶段的口腔健康。第二个目标 我们将确定Aβ的唾液分泌是否是口腔生态失调和口腔健康下降所必需的， AD线。在第三个目标中，我们将确定口腔微生态失调是否是特别负责的。 小鼠口腔健康和大脑疾病表现的下降。这项研究将确定一个创新的 这一机制表明，口腔生态失调和功能障碍是疾病的特征， 有助于AD进展。我们希望发现唾液Aβ分泌有助于口腔生态失调， 改变口腔微生物组足以改善大脑中的疾病表现。这将证明 一个新的双向理解的疾病涉及口脑轴。