Emerging Roles of Higher-order Polyamines During Tauopathies

高阶多胺在 Tau蛋白病中的新作用

• 批准号: 10251367
• 负责人: Daniel Carl Lee
• 金额: $ 47.1万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251367
• 关键词: Acetylation; Affect; Age; Alzheimer' s Disease; American; Anabolism; Animal Model; Arginine; Autophagocytosis; Axon; Back; Behavioral; Caring; Catabolism; Cell Culture Techniques; Cells; Cessation of life; Cognition; DL-alpha-Difluoromethylornithine; Data; Dependovirus; Deposition; Diagnosis; Diet; Dietary Administration; Disease; Drug Targeting; Enzymes; Family; Functional disorder; Generations; Goals; Human; Inflammation; Knock-out; Knockout Mice; Knowledge; Learning; Length; Measures; Mediating; Medical; Memory; Metabolism; Microtubules; Modeling; Molecular Weight; Mus; Neurodegenerative Disorders; Neurons; Nitric Oxide; Nitric Oxide Synthase; Nutritional; Ornithine; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitor; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Polyamine Catabolism; Polyamines; Production; Protein Kinase; Proteins; Recovery; Regulation; Reporting; Role; Spermidine; Spermidine Synthase; Spermine; Spermine Synthase; Stains; Supplementation; System; Tauopathies; Testing; Therapeutic; Transferase; Transgenic Mice; age related; arginase; behavioral outcome; biological adaptation to stress; chronic traumatic encephalopathy; cost; cytokine; gene therapy; hippocampal atrophy; inflammatory marker; inhibitor/antagonist; mouse model; nitration; novel; ornithine decarboxylase antizyme; overexpression; response; success; tau Proteins; tau aggregation; tau-1; therapeutic target; transcription factor

Collectively tauopathies including Alzheimer’s disease (AD) impact close to 6 million Americans and cost over $200 billion in medical care. They devastate families and cause victims to lose their memory, their dignity and, finally, their identity. Currently no disease modify agents exist for treating tauopathies, and AD and spontaneous recovery is unknown; a diagnosis of tauopathy is a death sentence. Strategies proposed to reduce tau burden include increasing clearance, decreasing phosphorylation or nitration, reducing aggregation, and diminishing inflammation, among others. Arginine metabolism is poised at a critical branch-point and serves as a precursor for nitric oxide generation from nitric oxide synthases or polyamine production from arginase (Arg1). Our data indicates that Arg1 overexpression in a mouse model of tauopathy reduces multiple aspects of the tau phenotype; phospho-tau deposition, Gallyas staining, hippocampal atrophy, high molecular weight tau multimers, tau nitration, cytokine markers of inflammation, inhibitors of autophagy, and protein kinase activation. Many of these effects can also be demonstrated in cell culture. We also show that higher- order polyamines directly block tau aggregation and promote microtubule assembly in solution at physiological concentrations, but acetylated polyamines fail to mimic this affect. Several distinct effects of this manipulation could mediate these remarkable benefits of Arg1 over expression and polyamine metabolism. The goal of this application is to better understand how polyamines contribute to the benefits of reducing the tau phenotype, and identify other potential targets for treating tauopathies and possibly AD. Utilizing gene therapy, mouse models of tauopathy, and knockout models we will test four aims. 1) Determine if Increased Polyamines Diminish Tau Pathology. 2) Determine if Reduced Polyamines Enhance Tau Pathology. 3) Test if Pharmacological Nutritional Modulation of Polyamines Regulates Tau Pathology and 4) Test if the Deletion of SSAT Reduces Tau Pathology. Success in these aims will increase our knowledge regarding the role of polyamines metabolism in regulating the tau phenotype. Our goal is to identify additional therapeutic targets that could be regulated by pharmacological agents to arrest or slow the progression of the tau deposition in humans with neurodegenerative disease.

包括阿尔茨海默病（AD）在内的牛头病变总共影响了近600万美国人，造成的损失超过100万美元

项目成果

Arginase 1 Insufficiency Precipitates Amyloid-β Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis.

• DOI: 10.3389/fimmu.2020.582998
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Ma C;Hunt JB;Selenica MB;Sanneh A;Sandusky-Beltran LA;Watler M;Daas R;Kovalenko A;Liang H;Placides D;Cao C;Lin X;Orr MB;Zhang B;Gensel JC;Feola DJ;Gordon MN;Morgan D;Bickford PC;Lee DC
• 通讯作者: Lee DC

Myeloid Arginase 1 Insufficiency Exacerbates Amyloid-β Associated Neurodegenerative Pathways and Glial Signatures in a Mouse Model of Alzheimer's Disease: A Targeted Transcriptome Analysis.

• DOI: 10.3389/fimmu.2021.628156
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Ma C;Hunt JB;Kovalenko A;Liang H;Selenica MB;Orr MB;Zhang B;Gensel JC;Feola DJ;Gordon MN;Morgan D;Bickford PC;Lee DC
• 通讯作者: Lee DC