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
基本信息
- 批准号:10723848
- 负责人:
- 金额:$ 12.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:16S ribosomal RNA sequencingAffectAllelesAlzheimer disease preventionAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease therapeuticAmyloid beta-ProteinAmyloid beta-Protein PrecursorAntifungal AgentsAnxietyAspartic EndopeptidasesBacteriaBacterial AdhesinsBehaviorBiological Response ModifiersBlocking AntibodiesBlood - brain barrier anatomyBlood CirculationBrainC57BL/6 MouseCandida albicansCause of DeathCellsCerebrumCharacteristicsChronicComplementDataDementiaDepositionDevelopmentDiagnosisDiseaseDisease ProgressionDoseEnterobacteriaceaeEnzyme-Linked Immunosorbent AssayFilamentFrightGastritisGastrointestinal tract structureGenesGenotypeGenus staphylococcusGranulomaHarvestHistologicHistologyHumanImmuneImmune EvasionImmune responseInfectionInflammatoryInterferonsIntestinesIntravenousInvadedLinkLyticMemory LossMemory impairmentModelingMonitorMorphologyMusNeoplasm MetastasisNeurofibrillary TanglesNeuroimmuneNeuroimmunomodulationNeurologic DysfunctionsOralPathogenesisPathogenicityPathologicPeptidesPhysiologicalProteolysisProteomePublic HealthPublishingRecurrenceResearchRoleSamplingSenile PlaquesSiteStructureSurfaceTauopathiesTestingTissuesToxinTransgenic MiceUnited StatesVirulence FactorsWestern BlottingYeastsapolipoprotein E-4behavior testblood-brain barrier penetrationbrain sizecandidemiacognitive functioncytokinedisease phenotypeenteritisfungusgut bacteriagut colonizationgut inflammationintravenous administrationmigrationmouse modelmutantnovelpreventresponsesuccesssynthetic polymer Bioplextau-1translational modeltransmission processyeast infection
项目摘要
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
项目成果
期刊论文数量(0)
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Lynn Bimler其他文献
Lynn Bimler的其他文献
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