Link between early gut dysfunction and amyloid beta aggregation in Alzheimer's Disease related dementia

早期肠道功能障碍与阿尔茨海默病相关痴呆中β淀粉样蛋白聚集之间的联系

基本信息

批准号：
10407451
负责人：
Bhanu Priya Ganesh
金额：
$ 52.42万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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：
2021-06-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10407451
关键词：
AD transgenic mice Acute Affect Age Age-Months Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Amyloid Amyloid Proteins Amyloid beta-Protein Amyloid deposition Anabolism Animals Antigens Bacteria Bilateral Biological Process Blood Blood Circulation Brain Breeding Cells Cognitive deficits Communication Complement Complex Data Dementia Dextrans Diet Disease Disease Progression E-Cadherin Environment Etiology Foundations Functional disorder Gastrointestinal tract structure Homeostasis Human Immune system Impaired cognition Impairment Inflammation Inflammatory Intestines Knockout Mice Lactobacillus reuteri Life Link Maintenance Malabsorption Syndromes Mass Spectrum Analysis Measures Mediating Memory impairment Microbe Microbial Biofilms Mucous body substance Mus Myelin Neuraxis Neurodegenerative Disorders Neurons Oligodendroglia Onset of illness Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Peripheral Production Proteins Research Role Secondary to Senile Plaques Severities Sodium Staphylococcus aureus Symptoms Testing Tg2576 Tight Junctions Transgenic Mice Transgenic Model Transgenic Organisms abeta accumulation abeta deposition absorption aged behavior test beta amyloid pathology cerebral amyloidosis confocal imaging cytokine dysbiosis extracellular gastrointestinal epithelium gut homeostasis gut inflammation gut-brain axis improved insight intrinsic factor-cobalamin receptor microbiota mouse model mutant myelination novel nutrient absorption prevent preventive intervention prion-like receptor repaired response two-photon β-amyloid burden

项目摘要

PROJECT SUMMARY In recent years, it has become apparent that a “gut-brain” axis exists where communication occurs between the gut, its microbiota, the immune system and the brain. Although not fully understood, this axis has a major role in the onset and severity of many neurodegenerative diseases (NDD). In direct response to PAR-19-070, we propose to study the role of the gut-brain axis in Alzheimer’s disease (AD). AD is a common, progressive and devastating NDD characterized by memory impairment and cognitive decline. The most prominent pathological hallmarks of the disease are the extracellular accumulation of amyloid β (Aβ) peptides in the form of plaques. Non-identical amyloid proteins may accelerate reciprocal amyloid aggregation in a prion-like fashion. A growing body of evidence suggests that intestinal bacteria produces amyloid-like proteins that form biofilms. Loss of gut barrier integrity leads to bacterial breach and bacterial amyloid translocation that potentially causes inflammation and accelerate central-Aβ pathology that then contribute to NDD progression from gut to brain. Gut inflammation can also impair nutrient absorption. B12 influences myelin homeostasis and its malabsorption accelerates brain amyloidosis. Myelin loss and the inability of the oligodendrocytes, the cells responsible for the production and maintenance of myelin, to repair myelin damage, are central features of AD and are associated with dementia. B12 biosynthesis is confined to certain bacteria. Luminal B12 is absorbed by gut epithelial receptors and stored as transcobalamine-B12 complex (tBC). For B12 to actively take part in biological processes, it needs to be stored in the form of tBC. The pathologic cascade linking gut pathology to Aβ deposition is not understood. We will develop the idea that early acute gut inflammation leads to impaired gut integrity and B12 malabsorption leading to accelerated central-Aβ pathology. It is this “loss of gut barrier integrity” that sustains an environment conductive for onset and progression of Aβ aggregation related dementias. We propose to test the following hypothesis that gut dysfunction precedes amyloid-β aggregation in the AD brain. (i) Restoring receptor- mediated B12 absorption and (ii) improving integrity of the gut by “early” beneficial bacterial therapy will lead to reduced Aβ aggregation “later” in the transgenic AD mice brain. In Aim 1, we will determine if gut inflammation early in life accelerates Aβ aggregation in the brain. If brain Aβ aggregation and disease progression are secondary to early gut abnormalities, then creating gut inflammation early in life will lead to loss of gut integrity, increased bacterial breach and subsequent bacterial amyloid translocation and earlier brain Aβ aggregation. In Aim 2, we will determine if B12 receptor loss and/or B12 malabsorption leads to impaired myelination and earlier Aβ aggregation. In Aim 3, we will determine if preventing gut dysfunction and restoring gut homeostasis with a beneficial bacterium (a B12 producer) improves absorption, gut integrity and delays the onset or progression of AD. These studies represent a “translatable” foundation for the potential treatment of neurodegenerative diseases in humans

项目概要近年来，越来越明显的是，“肠脑”轴存在于大脑之间进行沟通的地方。尽管尚未完全了解，但该轴在肠道、微生物群、免疫系统和大脑中发挥着重要作用。许多神经退行性疾病 (NDD) 的发病和严重程度作为对 PAR-19-070 的直接回应，我们提议研究肠脑轴在阿尔茨海默病（AD）中的作用，阿尔茨海默病是一种常见的、进行性的、进行性的疾病。破坏性NDD以记忆障碍和认知能力下降为最突出的病理特征。该疾病的标志是β淀粉样蛋白(Aβ)肽以斑块形式在细胞外积聚。不同的淀粉样蛋白可能以类似朊病毒的方式加速淀粉样蛋白的相互聚集。大量证据表明，肠道细菌会产生淀粉样蛋白，从而形成肠道生物膜。屏障完整性导致细菌破坏和细菌淀粉样蛋白易位，可能导致炎症并加速中枢 Aβ 病理学，从而导致 NDD 从肠道炎症进展到大脑。 B12 还会损害营养物质的吸收，影响髓磷脂稳态，其吸收不良会加速大脑的吸收。淀粉样变性。髓鞘质丧失和少突胶质细胞（负责生产和治疗的细胞）的丧失能力。维持髓磷脂以修复髓磷脂损伤是 AD 的核心特征，并且与痴呆有关。 B12 生物合成仅限于某些细菌，Luminal B12 被肠道上皮受体吸收并储存。作为转钴胺-B12 复合物 (tBC)，维生素 B12 需要积极参与生物过程。我们尚不清楚肠道病理学与 Aβ 沉积之间的病理级联反应。将提出这样的观点：早期急性肠道炎症会导致肠道完整性受损和 B12 吸收不良导致中枢 Aβ 病理加速，正是这种“肠道屏障完整性的丧失”维持了环境。有助于 Aβ 聚集相关痴呆的发生和进展。我们建议测试以下内容。假设肠道功能障碍先于 AD 大脑中的 β 淀粉样蛋白聚集 (i) 恢复受体。介导 B12 吸收，以及 (ii) 通过“早期”有益细菌疗法改善肠道完整性将导致“稍后”转基因 AD 小鼠大脑中 Aβ 聚集减少。在目标 1 中，我们将确定生命早期的肠道炎症是否会加速大脑中 Aβ 的聚集。聚集和疾病进展是早期肠道异常的继发因素，然后引起肠道炎症生命早期会导致肠道完整性丧失、细菌破裂增加以及随后的细菌淀粉样蛋白易位和早期大脑 Aβ 聚集在目标 2 中，我们将确定 B12 受体是否丢失和/或 B12。吸收不良会导致髓鞘形成受损和 Aβ 早期聚集。在目标 3 中，我们将确定是否可以预防。肠道功能障碍和用有益细菌（B12 生产者）恢复肠道稳态可改善吸收，这些研究为 AD 的“可转化”奠定了基础。人类神经退行性疾病的潜在治疗方法