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

阿尔茨海默病(AD)是美国第六大死因，也是#年唯一的死因 不能有效预防、治疗或治愈的前十名。最近的证据表明阿尔茨海默病可能是 与真菌脑部感染有关。为了严格研究这种可能性，我们建立了一个脑真菌病模型。 通过静脉注射致病酵母白色念珠菌，它通过血脑屏障进入 确定为脑实质感染。由此导致的脑真菌病导致轻微的记忆障碍和真菌 诱导的胶质肉芽肿(FIGG)由小胶质聚集、淀粉样蛋白β(aβ)沉积和淀粉样蛋白组成 酵母聚集体周围的前体蛋白(APP)。这种结构本质上复制了AD的特点 老年斑，但脑真菌病和记忆丧失是一过性的，不会持续超过10天 单一静脉感染。相比之下，阿尔茨海默病涉及许多老年斑和肌萎缩侧索硬化症 在与进行性、不可逆转的慢性脑真菌病有关的情况下，多年积累 痴呆症。这增加了白色念珠菌可能持续存在于偏远组织部位的关键可能性，例如 肠道，它可能会周期性地从那里动员起来，慢性地再次感染大脑。作为两种白色念珠菌 胃肠道的定植和源自胃肠道的低水平念珠菌血症已在#年记录在案。 我们假设慢性白色念珠菌肠炎导致真菌细胞低水平传播到 血流和持续性脑真菌病。来检验这一假设，并建立一个更具翻译性的 在相关慢性模型中，我们用白念珠菌酵母菌灌胃给野生型C57BL/6小鼠。我们 发现活酵母在灌胃后2天即可从脑中回收，并至少持续到第58天 而这种持久性在人类APOE4转基因小鼠中发生了改变，这些转基因小鼠表达了人类APOE的等位基因 与三分之二的AD病例有关。此外，这些菌落是多菌的，由酵母和 细菌，这一观察结果与最近发表的分析和我们自己对AD大脑的培养相一致 展示涉及真菌和细菌的多菌脑部感染。与我们之前的IV一致 模型，慢性感染的WT小鼠出现脑aβ1-40和1-42升高，并且这两种基因都存在 有异常行为的人。为了进一步确定该模型作为AD的翻译模型的潜力，我们 提出以下目标：(1)确定脑组织的病理和生理反应 多菌感染，(2)确定肠道真菌和细菌向脑转移的机制，(3) 目的：探讨胃炎对肠道真菌和细菌脑转移的影响。通过这件事 我们将确定这种感染是否会产生AD表型，这种感染是如何侵袭大脑和 在宿主中持续存在，并参与真菌清除的免疫机制。这项研究具有开创性。 对于AD领域，建议使用抗真菌药物治疗和预防AD，阐明了新的 神经免疫机制，为阿尔茨海默病的治疗和机制研究提供了前所未有的模型。

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.