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.

概括 尽管阿尔茨海默病 (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 展示了大脑外部的病理生理学，这表明疾病的过程更加复杂。 现在许多研究表明口腔的全身变化也有影响。 人类患者的唾液 Aβ 浓度升高，并报告了与 AD 的关系。 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危险因素。 对于 AD 而言，这表明 AD 和牙周健康可能存在两种不同的相互关系。 AD、APP/PS1 和 AppNL-G-F 小鼠的转基因小鼠淀粉样变性模型中，我们不仅验证了 Aβ 的分泌 唾液，但与疾病相关的独特口腔微生物组和牙釉质变薄以及蛀牙增加相比 根据这些发现和其他人之前的工作，我们追求口腔。 变化是导致疾病进展的 AD 的外围表现。 AppNL-G-F 小鼠系列在第一个目标中全面定义跨年龄和疾病阶段的口腔健康。 我们将确定口腔菌群失调和口腔健康下降是否需要唾液分泌 Aβ 在第三个目标中，我们将确定口腔菌群失调是否是造成这种情况的具体原因。 这项研究将定义小鼠口腔健康状况下降和大脑疾病的表现。 机制表明口腔生态失调和功能障碍是疾病的一个特征， 我们期望发现唾液 Aβ 分泌会导致口腔菌群失调和 改变口腔微生物群足以改善大脑中的疾病表现。 对涉及口脑轴的疾病的新的双向理解。