Chronic Murine Cerebral Mycosis: Pathogenesis, Neuroimmune Response, and Relevance to Alzheimer's Disease

慢性鼠脑真菌病：发病机制、神经免疫反应以及与阿尔茨海默病的相关性

• 批准号: 10723848
• 负责人: Lynn Bimler
• 金额: $ 12.9万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723848
• 关键词: 16S ribosomal RNA sequencing; Affect; Alleles; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease therapeutic; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antifungal Agents; Anxiety; Aspartic Endopeptidases; Bacteria; Bacterial Adhesins; Behavior; Biological Response Modifiers; Blocking Antibodies; Blood - brain barrier anatomy; Blood Circulation; Brain; C57BL/6 Mouse; Candida albicans; Cause of Death; Cells; Cerebrum; Characteristics; Chronic; Complement; Data; Dementia; Deposition; Development; Diagnosis; Disease; Disease Progression; Dose; Enterobacteriaceae; Enzyme-Linked Immunosorbent Assay; Filament; Fright; Gastritis; Gastrointestinal tract structure; Genes; Genotype; Genus staphylococcus; Granuloma; Harvest; Histologic; Histology; Human; Immune; Immune Evasion; Immune response; Infection; Inflammatory; Interferons; Intestines; Intravenous; Invaded; Link; Lytic; Memory Loss; Memory impairment; Modeling; Monitor; Morphology; Mus; Neoplasm Metastasis; Neurofibrillary Tangles; Neuroimmune; Neuroimmunomodulation; Neurologic Dysfunctions; Oral; Pathogenesis; Pathogenicity; Pathologic; Peptides; Physiological; Proteolysis; Proteome; Public Health; Publishing; Recurrence; Research; Role; Sampling; Senile Plaques; Site; Structure; Surface; Tauopathies; Testing; Tissues; Toxin; Transgenic Mice; United States; Virulence Factors; Western Blotting; Yeasts; apolipoprotein E-4; behavior test; blood-brain barrier penetration; brain size; candidemia; cognitive function; cytokine; disease phenotype; enteritis; fungus; gut bacteria; gut colonization; gut inflammation; intravenous administration; migration; mouse model; mutant; novel; prevent; response; success; synthetic polymer Bioplex; tau-1; translational model; transmission process; yeast infection

Alzheimer’s Disease (AD) is the sixth leading cause of death in the United States and the only cause of death in the top ten that cannot be effectively prevented, treated, or cured. Recent evidence suggests that AD may be linked to fungal brain infections. To rigorously study this possibility, we established a model of cerebral mycosis by intravenously (IV) injecting the pathogenic yeast Candida albicans, which transits the blood brain barrier to establish a parenchymal brain infection. The resulting cerebral mycosis induces mild memory deficits and fungal induced glial granulomas (FIGGs) consisting of microglial aggregates, amyloid β (aβ) deposits, and amyloid precursor protein (APP) surrounding yeast aggregates. This structure essentially duplicates AD’s characteristic senile plaques, but the cerebral mycosis and memory loss are transient, not persisting beyond 10 days after a single intravenous infection. In contrast, AD involves numerous senile plaques and tauopathy that presumably accrue over many years in the setting of chronic cerebral mycosis that is linked to progressive, irreversible dementia. This raises the key possibility that C. albicans might persist in a remote tissue site, such as the intestines, from which it might periodically mobilize to chronically re-infect the brain. As both C. albicans colonization of the GI tract and low-level candidemia deriving from the GI tract have been documented in humans, we hypothesize that chronic C. albicans enteritis leads to low-level transmission of fungal cells into the bloodstream and persistent cerebral mycosis. To test this hypothesis and establish a more translationally relevant chronic model, we administered yeast from C. albicans to wildtype C57BL/6 mice via oral gavage. We found that live yeast are recoverable from the brain as soon as 2 days post gavage and out to at least day 58 and this persistence is altered in human APOE4 transgene mice, which express the human allele of APOE that is linked to two-thirds of AD cases. Additionally, these colonies were polymicrobial, consisting of both yeast and bacteria, an observation that is consistent with recent published analysis and our own cultures of AD brains that demonstrate polymicrobial brain infections involving both fungi and bacteria. Consistent with our previous IV model, chronically infected WT mice present with elevated brain aβ 1-40 and 1-42 and both genotypes present with abnormal behavior. To further determine the potential of this model as a translational model for AD, we propose the following aims: (1) to determine the histopathological and physiological brain response to polymicrobial infection, (2) To determine the mechanism of metastasis of gut fungi and bacteria to the brain, (3) to determine effect of gastric inflammation on metastasis of gut fungi and bacteria to the brain. Through this study we will establish if this infection produces an AD phenotype, how this infection invades the brain and persists in the host, and the immune mechanisms involved in fungal clearance. This research is groundbreaking for the AD field, suggesting the use antifungals as treatment and prevention for AD, elucidating novel neuroimmune mechanisms, and producing an unprecedented model for AD therapeutic and mechanistic studies.

阿尔茨海默氏病（AD）是美国第六大死亡原因，是唯一的死亡原因 无法有效预防，治疗或治愈的前十名。最近的证据表明广告可能是 与真菌脑感染有关。为了严格研究这种可能性，我们建立了一个脑膜病模型 通过静脉注射（IV）注射致病性酵母念珠菌，该白色念珠菌将血脑屏障转移到 建立副脑脑感染。由此产生的脑膜片化会诱发轻度记忆力缺陷和真菌 由小胶质骨料，淀粉样蛋白β（Aβ）沉积物和淀粉样蛋白组成的诱导神经胶质肉芽肿（FIGGS） 酵母聚集体周围的前体蛋白（APP）。这种结构本质上是复制AD的特征 老年斑块，但脑膜病和记忆力丧失是短暂的，在a之后的10天后持续了10天 单静脉感染。相比之下，广告涉及大概是许多老年斑块和陶氏菌 在慢性脑膜病的情况下，多年来与渐进的，不可逆的 失智。这提出了关键的可能性，白色念珠菌可能会持续在偏远的组织部位，例如 肠子，它可能会定期动员长期重新感染大脑。作为白色念珠菌 gi道的定植和从胃肠道衍生的低水平候选血症已记录在 人类，我们假设慢性白色念珠菌肠炎导致真菌细胞低水平的传播 血液和持续的脑膜病。检验这一假设并更翻译 相关的慢性模型，我们通过口服饲料从白色念珠菌到野生型C57BL/6小鼠的酵母。我们 发现野马后2天，活酵母可从大脑中回收，至少到第58天 这种持久性在人类apoe4变形小鼠中发生了改变，这表达了人类的apoe等位基因 与三分之二的AD病例有关。此外，这些菌落是多数菌的，由酵母和 细菌，这一观察结果与最近发表的分析以及我们自己对广告大脑的文化一致 展示了涉及真菌和细菌的多数型脑感染。与我们以前的IV一致 模型，长期感染的WT小鼠，脑Aβ1-40和1-42的升高，两种基因型存在 具有异常行为。为了进一步确定该模型作为AD翻译模型的潜力，我们 提案以下目的：（1）确定组织病理学和身体大脑对 多因素感染，（2）确定肠道真菌和细菌向大脑的转移机理，（3） 确定胃感染对肠道真菌和细菌向大脑转移的影响。通过这个 研究我们将确定这种感染是否产生AD表型，这种感染如何引入大脑和 持续存在于宿主，以及涉及真菌清除的免疫机制。这项研究是开创性的 对于广告领域，建议使用抗真菌剂作为AD的治疗和预防，阐明了新颖的新型 神经免疫机制，并为AD疗法和机械研究生成了前所未有的模型。