Oxidative Dysfunction of LRP at the Blood-brain Barrier in Alzheimer's Disease

阿尔茨海默病中血脑屏障 LRP 的氧化功能障碍

基本信息

批准号：
7371300
负责人：
WILLIAM A BANKS
金额：
$ 31.06万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7371300
关键词：
3-nitrotyrosine 4 hydroxynonenal ATP phosphohydrolase Acetylcysteine Address Affect Alzheimer&apos s Disease Amyloid Amyloid Beta A4 Precursor Protein Animals Antibodies Antioxidants Antisense Oligonucleotides Binding Blood Blood - brain barrier anatomy Blood Vessels Blood capillaries Brain Cessation of life Endothelial Cells Epidemiologic Studies Event Functional disorder Genes Glutamate Transporter Glutamates Goals Hepatocyte Human Hydrophobicity Impaired cognition Impairment In Vitro LDL-Receptor Related Protein 1 Laboratories Laboratory mice Length Ligands Lipid Peroxidation Lipoprotein Receptor Macroglobulins Measures Methionine Modeling Modification Mus Mutation Na(+)-K(+)-Exchanging ATPase Norleucine Numbers Oxidants Oxidative Stress P-Glycoprotein P-Glycoproteins Patients Peptides Phosphorothioate Oligonucleotide Play Poison Protein Overexpression Proteins Pump Rate Relative (related person)Resistance Risk Rodent Role Series System Testing Therapeutic Intervention Thioctic Acid Tissues Transgenic Organisms Upper arm Vitamin E Work amyloid peptide analog base brain tissue capillary efflux pump in vitro Model in vivo indexing mild neurocognitive impairment mind control monolayer mouse model mutant neurotoxic oxidation research study senescence unpublished works

项目摘要

DESCRIPTION (provided by applicant): The neurovascular hypothesis states that an impaired brain-to-blood efflux of amyloid ¿ protein (ABP) at the vascular blood-brain barrier (BBB) is an important mechanism underlying ABP accumulation and cognitive impairments in patients with Alzheimer's disease (AD). Low-density lipoprotein receptor-related protein-1 (LRP) has been identified as the major efflux pump at the BBB for ABP. Zlokovic and co-workers have shown that LRP is deficient in the BBB of patients with AD and of Hsiao mice that overexpress amyloid precursor peptide (APP). We have shown that ABP efflux is impaired at the BBB in animals which overexpress ABP and that knockdown of APP expression with antisense restores BBB efflux of ABP. This suggests that ABP poisons its own transporter, LRP. Our goal is to determine whether the mechanism of impaired efflux of ABP is caused by ABP-induced oxidative damage to LRP. ABP, especially in its oligomeric form, induces oxidative stress and by this mechanism impairs the function of transporters other than LRP in non-BBB tissues. LRP in non-BBB tissues is already known to be readily oxidized and its ability to transport its other ligands in those tissues is impaired in its oxidative state. Our hypothesis is that ABP impairs its own efflux at the BBB by oxidizing LRP. We will test this hypothesis in 3 Specific Aims: Specific Aim 1: To determine in vivo whether mice that do overexpress APP have an oxidized LRP and whether ABP efflux can be restored to normal rates by treatments which reduce ABP or by antioxidants. Specific Aim 2: To determine the role of ABP and oxidation in impairing BBB efflux of ABP in vitro in a BBB monolayer model that uses brain endothelial cells derived from mice that do not overexpress APP. Specific Aim 3: To determine the status of oxidative modification of LRP in human brain tissue obtained at short post mortem intervals (PMI; specifically, < 4h after death) from patients with AD and mild cognitive impairment (MCI) relative to that from control brain tissue and correlate this information to the level and oligomeric status of ABP1-42 in those same brains and to compare this to a similar analysis for the mice that overepress APP.

描述（由申请人提供）：神经血管假说指出，淀粉样蛋白的大脑到血液的流出受损 ¿血管血脑屏障（BBB）上的低密度脂蛋白受体相关蛋白（LRP）是ABP积累和阿尔茨海默病（AD）患者认知障碍的重要机制。 Zlokovic 及其同事发现，LRP 在 AD 患者和过度表达淀粉样前体肽的 Hsiao 小鼠的 BBB 中缺乏。 (APP)。我们已经证明，在过度表达 ABP 的动物中，BBB 的 ABP 流出受到损害，并且用反义蛋白敲低 APP 的表达可以恢复 ABP 的 BBB 流出。我们的目标是确定 ABP 会毒害其自身的转运蛋白。 ABP 外流受损的机制是否是由 ABP 诱导的 LRP 氧化损伤（尤其是其寡聚形式）引起的，并通过这种机制诱导氧化应激。损害非 BBB 组织中 LRP 以外的转运蛋白的功能众所周知，非 BBB 组织中的 LRP 很容易被氧化，并且其在这些组织中转运其他配体的能力在其氧化状态下受到损害。通过氧化 LRP 损害其自身在 BBB 的流出，我们将在 3 个具体目标中检验这一假设：具体目标 1：确定体内过度表达 APP 的小鼠是否具有氧化的 LRP 以及 ABP 流出是否可以通过降低 ABP 的治疗或抗氧化剂恢复到正常水平具体目标 2：在使用脑内皮细胞的 BBB 单层模型中确定 ABP 和氧化在体外损害 ABP 的 BBB 流出中的作用。源自不过度表达 APP 的小鼠的细胞具体目标 3：确定死后短时间内获得的人脑组织中 LRP 的氧化修饰状态。 AD 和轻度认知障碍 (MCI) 患者的时间间隔（PMI；具体来说，死后 < 4 小时）相对于对照脑组织的时间间隔，并将这些信息与相同大脑中 ABP1-42 的水平和寡聚状态相关联，并进行比较这与过度抑制 APP 的小鼠的类似分析相同。