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.

阿尔茨海默病（AD）是美国第六大死亡原因，也是美国唯一的死亡原因