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

• 批准号: 10618370
• 负责人: Bhanu Priya Ganesh
• 金额: $ 52.89万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 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/10618370
• 关键词: AD transgenic mice; Acceleration; Acute; Affect; Age; Age Months; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid; Amyloid Proteins; Amyloid beta-Protein; Amyloid deposition; Anabolism; Animals; Antigens; Bacteria; Bilateral; Biological Process; Blood; Brain; Brain Diseases; Breeding; Cells; Central Nervous System; Circulation; Cognitive deficits; Communication; Complement; Complex; Data; Dementia; Demyelinations; Dextrans; Diet; Disease; Disease Progression; E-Cadherin; Environment; Etiology; Fermentation; Foundations; Functional disorder; Gastrointestinal tract structure; Homeostasis; Human; Immune system; Impaired cognition; Impairment; Inflammation; Inflammatory; Intervention; 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; Myelin Sheath; Neurodegenerative Disorders; Neurons; Oligodendroglia; Onset of illness; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Peripheral; Prevention strategy; 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; prion-like; receptor; receptor expression; repaired; response; two-photon; β-amyloid burden

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

项目总结 近年来，一个明显的事实是，存在着一个“肠道-大脑”轴，在这个轴上， 肠道、微生物区系、免疫系统和大脑。尽管还没有完全理解，但这个轴在 许多神经退行性疾病(NDD)的发病和严重程度。为了直接回应PAR-19-070，我们 建议研究肠道-脑轴在阿尔茨海默病(AD)中的作用。广告是一种普通的、递进的和 以记忆受损和认知衰退为特征的破坏性NDD。最突出的病理 这种疾病的特征是淀粉样蛋白(Aβ，Aβ)多肽以斑块的形式在细胞外积聚。 不同的淀粉样蛋白可能会以类似于普里恩的方式加速淀粉样蛋白的相互聚集。一个不断增长的 大量证据表明，肠道细菌产生淀粉样蛋白，形成生物膜。失去胆量 屏障的完整性会导致细菌破裂和细菌淀粉样蛋白移位，从而可能导致炎症 并加速中央-Aβ病理，从而促进新城疫从肠道到大脑的进展。肠炎 也会损害养分的吸收。B12影响髓鞘稳态及其吸收不良加速大脑 淀粉样变性。髓鞘丢失和少突胶质细胞的无能，这些细胞负责产生和 维护髓鞘，修复髓鞘损伤，是AD的中心特征，与痴呆症有关。 B12的生物合成仅限于某些细菌。鲁米那B12被肠道上皮受体吸收并储存 即转钴胺-B12复合体(TBC)。要让B12积极参与生物过程，它需要 以TBC的形式存储。将肠道病理与Aβ沉积联系起来的病理级联尚不清楚。我们 会认为早期急性肠炎会导致肠道完整性受损和B12吸收不良 导致加速的中央-Aβ病理。正是这种“肠道屏障完整性的丧失”维持了环境 有助于Aβ聚集性痴呆的发生和发展。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完整性 会导致Aβ在转基因AD小鼠大脑中聚集减少。 在目标1中，我们将确定生命早期的肠道炎症是否会加速Aβ在大脑中的聚集。If Brain Aβ 聚集和疾病进展是早期肠道异常继发的，然后造成肠道炎症 生命早期会导致肠道完整性丧失，细菌破裂增加，随后出现细菌淀粉样蛋白 易位与早期脑Aβ聚集在目标2中，我们将确定B12受体丢失和/或B12 吸收不良会导致髓鞘形成受损和Aβ提前聚集。在目标3中，我们将确定是否防止 肠道功能障碍和使用有益细菌(B12产生菌)恢复肠道动态平衡可以改善吸收， 肠道完整性和延缓阿尔茨海默病的发病或进展。这些研究代表了一个“可翻译”的基础 人类神经退行性疾病的潜在治疗