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Dissecting the role of 5LO in neurodegeneration associated with homocysteine

剖析 5LO 在与同型半胱氨酸相关的神经变性中的作用

基本信息

批准号：
9106037
负责人：
DOMENICO PRATICO
金额：
$ 195万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9106037
关键词：
Affect Alzheimer&apos s Disease Amino Acids Amyloid beta-Protein Animals Arachidonate 5-Lipoxygenase Behavior Biological Blood Brain Cells Chronic Clinical Clinical Trials Cognitive deficits DNA DNA Methylation DNA Modification Methylases Data Dementia Development Diet Disease Elderly Environmental Risk Factor Future Genes Goals Homocysteine Homocystine Hydrolysis Hyperhomocysteinemia Impaired cognition In Vitro Individual Intervention Knowledge Lesion Link Mediator of activation protein Memory impairment Metabolism Methionine Methylation Methyltransferase Minority Missense Mutation Mus Nerve Degeneration Neurobiology Neurodegenerative Disorders Neurofibrillary Tangles Neurons Onset of illness Pathogenesis Pathology Pathway interactions Peptides Persons Phenotype Plasma Probability Process Protein Precursors Proteins Publishing Reaction Risk Risk Factors Role S-Adenosylhomocysteine S-Adenosylmethionine Secondary to Senile Plaques Symptoms Tauopathies Testing Transgenic Mice Transgenic Model Translating Work age related aged base behavioral impairment cost disease phenotype economic cost effective therapy genetic approach genetic risk factor high risk in vivo inhibitor/antagonist modifiable risk mouse model novel novel therapeutic intervention prevent promoter public health relevance tau Proteins tau phosphorylation translational approach

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common chronic neurodegenerative disorder associated with dementia in the elderly, affecting approximately 6-8% all person aged >65 years. Although an effective treatment for the disease is unavailable, intervention to control risk factors implicated in the disease onset can still redue the number of cases and the associated enormous economic cost. This fact has stimulated a large effort to identify those factors and to develop treatments to reduce and/or prevent them. Abnormal elevation of homocysteine (Hcy) levels is considered a risk factor that significantly increases the probability to develop AD. However, the mechanism(s) involved in this biologic effect remain to be fully investigated. Our preliminary data demonstrate that Hcy specifically up-regulates 5Lipoxygenase (5LO), a protein widely expressed in the brain where it modulates Aβ formation and tau metabolism, and that 5LO is required for the changes in the AD-like phenotype secondary to Hcy. Taken together, these findings provide the rationale and biologic basis of our working hypothesis: Hcy activates the 5LO pathway, which then results in an abnormal formation of Aβ peptides, an excessive tau phosphorylation and cognitive deficits. We will test this hypothesis by studying the essential role of 5LO in the development of the Aβ and tau neuropathologies, and behavior deficits in transgenic mouse models of AD during a chronic condition of elevated Hcy. We will next investigate the mechanisms whereby Hcy via the 5LO modulates Aβ/APP processing and tau metabolism in neuronal cells. Finally, we will ascertain these mechanisms in vivo by using a pharmacologic and a genetic approach. Our studies are novel and significant because they will establish a biological link between Hcy and 5LO in the context of the AD pathogenesis. They also will provide new mechanistic knowledge into the neurobiology of Hcy, and useful clues for new therapeutic approaches in individuals carrying this risk factor for developing the disease.