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

项目摘要 近年来，已经变得明显的是，“肠-脑”轴存在于大脑和大脑之间发生通信的地方。 肠道、肠道微生物群、免疫系统和大脑。尽管尚未完全理解，但这一轴心在以下方面发挥着重要作用： 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 建议研究肠-脑轴在阿尔茨海默病（AD）中的作用。AD是一种常见的，渐进的， 以记忆障碍和认知能力下降为特征的毁灭性NDD。最突出的病理 该疾病的特征是淀粉样蛋白β（Aβ）肽以斑块的形式在细胞外积累。 不相同的淀粉样蛋白可能以朊病毒样方式加速相互的淀粉样蛋白聚集。越来越 大量证据表明，肠道细菌产生淀粉样蛋白，形成生物膜。肠道缺失 屏障完整性导致细菌破坏和细菌淀粉样蛋白移位，这可能导致炎症 并加速中枢A β病理，然后导致NDD从肠道进展到大脑。肠道炎症 也会损害营养吸收。B12影响髓鞘稳态，其吸收不良加速大脑 淀粉样变性髓鞘损失和少突胶质细胞的无能，少突胶质细胞负责产生和 维持髓鞘以修复髓鞘损伤是AD的中心特征，并且与痴呆相关。 B12的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 作为转钴胺素-B12复合物（tBC）。为了使B12积极参与生物过程，它需要 以TBC的形式储存。肠道病理与Aβ沉积之间的病理级联反应尚不清楚。我们 我将发展这样一种观点，即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A β病变加速。正是这种“肠道屏障完整性的丧失”维持了一个环境 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 这一假说认为，AD脑中肠功能障碍先于淀粉样蛋白-β聚集。(i)恢复受体- 介导的B12吸收和（ii）通过“早期”有益细菌治疗改善肠道的完整性 将导致转基因AD小鼠脑中“稍后”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的Aβ聚集。如果脑Aβ 聚集和疾病进展继发于早期肠道异常，然后产生肠道炎症 生命早期将导致肠道完整性的丧失，增加细菌破坏和随后的细菌淀粉样蛋白 易位和早期脑Aβ聚集。在目标2中，我们将确定B12受体丢失和/或B12 吸收不良导致髓鞘形成受损和早期Aβ聚集。在目标3中，我们将确定是否预防 肠道功能障碍和用有益细菌（B12生产者）恢复肠道稳态改善吸收， 肠道完整性和延迟AD的发作或进展。这些研究代表了一个“可译”的基础， 人类神经退行性疾病的潜在治疗

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