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，也是美国唯一的死因。 十大无法有效预防、治疗或治愈的疾病。最近的证据表明，AD可能是 与脑部真菌感染有关为了严格研究这种可能性，我们建立了脑真菌病模型 通过静脉内（IV）注射病原性酵母白色念珠菌，其穿过血脑屏障， 造成脑实质感染由此产生的脑真菌病引起轻度记忆缺陷和真菌感染。 诱导的神经胶质肉芽肿（FIGGs），由小胶质细胞聚集体、淀粉样蛋白β（aβ）沉积物和淀粉样蛋白组成 前体蛋白（APP）围绕酵母聚集体。这种结构基本上复制了AD的特征 老年斑，但脑真菌病和记忆丧失是短暂的，不持续超过10天后， 单一静脉感染。相比之下，AD涉及许多老年斑和tau蛋白病， 在慢性脑真菌病的背景下多年累积， 痴呆这就提出了C.白色念珠菌可能在远处的组织部位持续存在，例如 它可能周期性地从肠道移动，慢性地重新感染大脑。作为两个C.白色 胃肠道的定植和源自胃肠道的低水平念珠菌血症已在 人类，我们假设慢性C.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。为了验证这一假设，并建立一个更合理的 相关慢性模型，给予C.白色念珠菌通过口服管饲法给予野生型C57 BL/6小鼠。我们 发现在管饲后2天以及至少到第58天，活酵母可从脑中回收 并且这种持久性在人APOE 4转基因小鼠中改变，所述转基因小鼠表达APOE的人等位基因， 与三分之二的AD病例有关。此外，这些菌落是多微生物的，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的AD大脑培养物一致， 证明了涉及真菌和细菌的多微生物脑感染。与我们之前的IV一致 模型中，慢性感染WT小鼠表现为脑α β 1-40和1-42升高，两种基因型均存在 行为异常为了进一步确定该模型作为AD转化模型的潜力，我们 提出以下目标：（1）确定组织病理学和生理学脑反应， 多种微生物感染，（2）确定肠道真菌和细菌向脑转移的机制，（3） 以确定胃炎症对肠道真菌和细菌向脑转移的影响。通过这个 研究我们将确定这种感染是否产生AD表型，这种感染如何侵入大脑， 持续存在于宿主中，以及参与真菌清除的免疫机制。这项研究是开创性的 对于AD领域，建议使用抗真菌剂作为AD的治疗和预防，阐明了新的 神经免疫机制，并产生一个前所未有的模型，AD治疗和机制的研究。

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.