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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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氏病（AD）是一种与年龄相关的神经退行性疾病，但持续的证据在大脑外展示病理生理学。这表明疾病的过程更复杂，系统性表现也是如此。现在的大量研究表明，口腔的变化具有与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，牙周疾病，牙齿脱落和整体口腔健康都是积极的危险因素对于广告。这表明AD和牙周健康可能具有相互关系。使用两个不同 AD，APP/PS1和APPNL-G-F小鼠的转基因小鼠淀粉样变性模型，我们不仅验证了Aβ分泌相比到野生型控件。基于这些发现和他人的先前工作，我们假设那个口腔腔变化是导致疾病进展的AD的外围表现。我们将继续使用 APPNL-G-F小鼠系列在第一个目标中完全定义了跨年龄和疾病阶段的口腔健康。在第二个目标我们将确定口腔失调和口腔健康状况下降是否需要Aβ的唾液分泌广告线。在第三个目标中，我们将确定口腔失调是否特别造成小鼠口腔健康和脑部疾病的表现下降。这项研究将定义创新的表明口腔营养不良和功能障碍的机制是疾病的特征有助于广告进展。我们希望发现唾液Aβ分泌有助于口腔营养不良和改变口腔微生物组足以改善大脑中的疾病表现。这将证明对涉及脑脑轴的疾病的新双向理解。