Innate immune dysregulation in Alzheimer's disease modeled in Drosophila

以果蝇为模型的阿尔茨海默病的先天免疫失调

• 批准号: 10259828
• 负责人: MARC TATAR
• 金额: $ 18.69万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259828
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animals; Automobile Driving; Backcrossings; Brain; Catabolism; Characteristics; Data; Disease; Disease Progression; Drosophila genus; Exposure to; Gene Expression; Genetic Epistasis; Histopathology; Human; Immune; Inflammation; Inflammatory; Inherited; Innate Immune Response; Innate Immune System; Knock-out; Locomotion; Measures; Mediating; Microbe; Modeling; Mutation; Natural Immunity; Nerve Degeneration; Nervous System Physiology; Pathogenicity; Pathology; Phenotype; Phosphorylation; Process; Production; Protein Isoforms; Research; Resistance; Smell Perception; Tauopathies; Testing; abeta accumulation; age related; aging brain; antimicrobial; antimicrobial peptide; fly; genetic manipulation; mortality; neuropathology; overexpression; pathogen; tau Proteins; tau dysfunction; tau mutation; trait; young adult

Summary We propose that tau modulates innate immunity and AMPs in the brain, and thereby contributes to progression of Alzheimer’s disease. We will test this idea with Drosophila, where tau dysregulation is produced by a human neurodegeneration-associated mutation introduced into the fly’s endogenous tau, as well as by classic tau over- expression. In both models, tau dysregulation causes age-dependent decline in locomotion and olfaction. Tau over- expression produces neuropathology, and we will assess these traits in our new tau-mutant model. Central to our proposal, we find that expression of genes for innate immunity are dramatically altered in the tau-mutant model. Elevated innate immune expression is a common feature of aging Drosophila, where data demonstrates it contributes to mortality and, potentially, to neurodegeneration. With our observations, we propose that tau dysregulation drives innate immune AMPs to a pathogenic level in the brain of aging Drosophila, causing age-dependent neurodegeneration. In this view, a similar process may well occur in humans that drives the accumulation of Ab. If so, AD might be managed in terms of what drives, regulates and dysregulates innate immunity in the aging brain

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