RLIP, Mitochondrial Dysfunction in Alzheimer’s Disease

RLIP，阿尔茨海默病中的线粒体功能障碍

基本信息

批准号：
10901025
负责人：
P. Hemachandra Reddy
金额：
$ 57.2万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
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：
2023-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10901025
关键词：
ATP phosphohydrolase Affect Age Agreement Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Amino Acids Amyloid beta-Protein Animal Model Animals Apoptotic Astrocytes Ataxia Autophagocytosis Autopsy Behavior Behavioral Binding Biochemical Bioenergetics Biogenesis Biology Brain CREBBP gene Cancer Etiology Cell Culture Techniques Cell Nucleus Cell membrane Cells Clathrin Cognition Cognitive Complex Couples DNA Data Defense Mechanisms Dendritic Spines Diabetes Mellitus Disease Disease Progression Down-Regulation EP300 gene Endocytosis Enzymes Epigenetic Process Exons Free Radical Formation Free Radicals Functional disorder Gene Expression Genes Genetic Transcription Genus Hippocampus Goals Heterozygote Hippocampus Human Immunofluorescence Immunologic Impaired cognition Impairment Inflammatory Investigation Knock-in Knock-in Mouse Knock-out Knockout Mice Late Onset Alzheimer Disease Learning Length Leptin Link Lipid Peroxidation Lipids Long-Term Potentiation Loss of Heterozygosity Memory Memory impairment Metabolic syndrome Microglia Mitochondria Modeling Molecular Motor Motor Activity Mus Mutate Mutation Nerve Degeneration Neurocognition Neurocognitive Neurodegenerative Disorders Neurons Omega-6 Fatty Acids Outcome Oxidative Regulation Oxidative Stress Pathogenesis Pharmacotherapy Phenotype Play Polyunsaturated Fatty Acids Prevalence Proteins Publishing Research Role Severities Short-Term Memory Signal Transduction Stress Structure Synapses Synaptic plasticity Testing Tissues Toxic effect Toxin Transgenic Mice Up-Regulation Wild Type Mouse Work Xenobiotic Metabolism age related aging population alpha Tubulin behavioral impairment behavioral phenotyping beta amyloid pathology drug development immunoreactivity improved insight mind control mitochondrial dysfunction mouse model mutant neuronal survival novel novel therapeutics overexpression oxidation presenilin-1 prevent protective effect response synaptic function tau mutation tau-1

项目摘要

PROJECT SUMMARY Alzheimer's disease (AD) is a neurodegenerative disorder that affects a large proportion of the aging population. Despite its prevalence, no specific treatments can prevent or treat this disease. Research on the pathophysiology of the disease and the testing of new drugs is limited to transgenic mouse models harboring mutated versions of AD-related genes, including APP, PSEN1, APOEɛ4, and ob (leptin). Since oxidative stress (OS) in the brain is believed to be involved in AD pathogenesis, markers of OS such as protein oxidation, lipid oxidation, DNA oxidation, glycoxidation, and mitochondrial dysfunction may also have utility as markers for AD. RalBP1 (Rlip) is a stress-activated protein that plays a crucial role in OS defense as the rate- determining enzyme in the efflux of the GSH-conjugated oxidative metabolites. While we have extensively characterized the role of Rlip as a centrally important oxidative stress-defense mechanism in the etiologies of cancer, metabolic syndrome, and diabetes, we have only recently begun to study its function in neurons. Our preliminary data and published suggests that the Rlip knockout in neuronal cells and Rlip mice developed strong mechanistic links with oxidative stress/mitochondrial dysfunction and synaptic damage in AD. Further, Rlip deficient mice and neurons have increased OS in the brain and downregulation of NRF2, which OS normally up-regulates. This dysregulated NRF2 response likely contributes to further exacerbated oxidative stress, impaired xenobiotic metabolism, and dysregulated mitochondrial functions in these mice. We provide intriguing preliminary evidence of Rlip deficiency in human postmortem AD brains and abnormalities of mitochondrial structure, function, and proteins in Rlip deficient mice and in Rlip deficient neurons in culture. Our preliminary studies show that Rlip depletion epigenetically regulates several AD-linked genes, including CREBBP, a gene implicated in neurocognition. The Rlip+/- model will allow us to develop an oxidative stress animal model of AD, which in turn will be helpful in the development of drugs for the treatment of AD and in conducting studies that will lead to novel findings on AD biology. Based on our preliminary findings, we hypothesize that Rlip deficiency causes oxidative stress, which exacerbates neurodegeneration and dysregulation of neurocognitive functions; therefore, reducing oxidative stress signaling through Rlip upregulation may improve mitochondrial and synaptic functions and cognitive behavior. Under the proposed Aims 1) we will study whether Rlip knockout mice have neurocognitive, histopathological, biochemical, and neuronal deficits resembling those seen in humanized Aβ knock-in (hAβ-KI) mice, and 2) whether Rlip upregulation ameliorates the phenotypic severity of the hAβ-KI model. These studies will offer novel insights into the regulation of oxidative stress defenses in AD and may lead to new treatments for AD.

项目摘要阿尔茨海默氏病（AD）是一种神经退行性疾病，影响很大的衰老人口。尽管率很高，但没有特定的治疗方法可以预防或治疗这种疾病。研究该疾病的病理生理学和新药的测试仅限于携带的转基因小鼠模型与AD相关基因的突变版本，包括App，PSEN1，APOEɛ4和OB（瘦素）。自氧化以来据信大脑中的压力（OS）参与AD发病机理，OS的标记，例如蛋白质氧化，脂质氧化，DNA氧化，糖氧化和线粒体功能障碍也可能具有实用性广告的标记。 RALBP1（RLIP）是一种应激激活的蛋白质，在OS防御中起着至关重要的作用，作为速率 - 确定GSH偶联的氧化物代谢物的外排中的酶。虽然我们有广泛的表征了rlip作为中心重要的氧化应力防御机制在病因中的作用癌症，代谢综合征和糖尿病，我们直到最近才开始研究其在神经元中的功能。我们的初步数据并发布了与AD中的氧化应激/线粒体功能障碍和突触损伤的牢固机械联系。更远， rip缺乏小鼠和神经元在大脑中的OS增加和NRF2的下调，其中OS 通常上调。这种失调的NRF2响应可能导致进一步加剧的氧化物这些小鼠的应激，异种代谢受损以及线粒体功能失调。我们提供人类后大脑中的撕裂缺乏的有趣初步证据和异常 rip缺乏小鼠的线粒体结构，功能和蛋白质以及培养中rip缺乏神经元中的线粒体结构。我们的初步研究表明，rlip部署表观遗传调节了几种广告连接基因，包括 CREBBP，与神经认知有关的基因。 RLIP +/-模型将使我们能够发展出氧化应力 AD的动物模型，反过来将有助于开发用于治疗AD和IN的药物进行研究，这将导致有关AD生物学的新发现。根据我们的初步发现，我们假设rlip缺乏会导致氧化应激，从而加剧了神经退行性的变化和神经认知功能的失调；因此，通过rlip降低氧化应激信号传导上调可以改善线粒体和突触功能以及认知行为。在拟议的下目的1）我们将研究rip敲除小鼠是否具有神经认知，组织病理学，生化和神经元定义了类似于人源化Aβ敲进（HAβ-KI）小鼠的类似上调可以改善HAβ-KI模型的表型严重程度。这些研究将提供新颖的见解进入AD中氧化应激防御措施的调节，并可能导致新的AD治疗方法。