The role of Clusterin in cerebral amyloid angiopathy

Clusterin 在脑淀粉样血管病中的作用

基本信息

批准号：
9765415
负责人：
John David Fryer
金额：
$ 34.23万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9765415
关键词：
APP-PS1 Abeta clearance Adult Affect Affinity Age-Months Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Amyloidosis Apolipoprotein E Apolipoproteins Astrocytes Behavior Binding Biochemistry Biological Assay Biology Blood Vessels Blood capillaries Blood flow Brain Cell Culture Techniques Cerebral Amyloid Angiopathy Cerebrovascular system Cerebrum Cessation of life Clinic Code Data Dementia Deposition Drainage procedure Electrophysiology (science)Extravasation Genes Genetic Genotype Glial Fibrillary Acidic Protein Hemorrhage Hippocampus (Brain)Histopathology Human In Vitro Individual Inflammation Intercellular Fluid Knockout Mice LDL-Receptor Related Protein 1 LDL-Receptor Related Protein 2 Lead Measures Mediating Metabolism Microdialysis Molecular Mus Mutation Neurofibrillary Tangles Neurons Pathologic Pathology Pathway interactions Patients Pharmacology Population Proteins Publishing Role Senile Plaques Smooth Muscle Myocytes Stroke Testing Therapeutic Toxic effect Transgenic Mice Variant Vascular Diseases Viral abeta deposition amyloid pathology astrogliosis brain parenchyma brain tissue cerebrovascular extracellular genetic risk factor genetic variant genome wide association study genome-wide human data human tissue in vivo malignant breast neoplasm mouse model new therapeutic target novel novel therapeutics overexpression plexin public health relevance receptor sulfated glycoprotein 2 targeted treatment tau Proteins

项目摘要

DESCRIPTION (provided by applicant): Alzheimer disease (AD) is the most common cause of dementia and is characterized by extracellular plaques formed by the deposition of amyloid-β (Aβ) peptide and intracellular tangles comprised of hyperphosphorylated forms of the tau protein. Another common pathology in AD is cerebral amyloid angiopathy (CAA), caused by Aβ deposition in the walls of cerebral vessels leading to vascular dysfunction and hemorrhage. The strongest genetic risk factor for both AD and CAA is ε4 allele of the apolipoprotein E (APOE) gene, but multiple recent genome-wide association studies have proven that a similar apolipoprotein, Clusterin (CLU), also confers risk for AD. The role of CLU in CAA is unknown, but we have strong evidence that CLU is critically involved in the formation of CAA. While much is known about apoE receptor biology, the only known receptor for Clu, LRP2/Megalin, is very poorly expressed in the adult brain, suggesting other receptors are present but undiscovered. We have found that Plexin A4 (PLXNA4) is a novel receptor that regulates the levels of extracellular CLU in mice and in humans. PLXNA4 levels are significantly decreased in mouse models of AD as well as human AD brain tissue compared to controls. The objective of this proposal is to define how CLU regulates Aβ metabolism and deposition in brain parenchyma and cerebrovasculature. Using a combination of cell culture, biochemistry, mouse genetics, pharmacology, and pathologically defined human tissue, we will determine how the CLU and PLXNA4 affect AD by studying functional endpoints such as histopathology, vascular dysfunction, neuritic dystrophy, electrophysiology, and behavior. Deciphering this pathway could lead to new therapeutic targets not only for AD, but also for stroke and breast cancer, given the emerging role of CLU in those respective fields.

描述（由申请人提供）：阿尔茨海默病（AD）是痴呆症的最常见原因，其特征是淀粉样蛋白-β（Aβ）肽沉积形成的细胞外斑块和由过度磷酸化形式的 tau 蛋白组成的细胞内缠结。 AD 的常见病理是脑淀粉样血管病 (CAA)，由 Aβ 沉积在脑血管壁引起，导致血管功能障碍和出血，这是 AD 和 AD 的最强遗传危险因素。 CAA 是载脂蛋白 E (APOE) 基因的 ε4 等位基因，但最近多项全基因组关联研究证明，类似的载脂蛋白 Clusterin (CLU) 也会导致 AD 风险。CLU 在 CAA 中的作用尚不清楚，但我们目前尚不清楚。有强有力的证据表明 CLU 与 CAA 的形成密切相关，尽管人们对 apoE 受体生物学了解很多，但唯一已知的 Clu 受体 LRP2/Megalin 在成人中的表达非常差。大脑中存在其他受体，但尚未发现。我们发现 Plexin A4 (PLXNA4) 是一种调节小鼠和人类细胞外 CLU 水平的新型受体，在 AD 小鼠模型和人类中，PLXNA4 水平显着降低。 AD 脑组织与对照相比，该提案的目的是结合细胞培养、生物化学、遗传学、药理学和病理学定义的人体组织，我们将通过研究组织病理学、血管功能障碍、神经营养不良、电生理学和行为等功能终点来确定 CLU 和 PLXNA4 如何影响 AD，破译该通路不仅可以带来新的治疗靶点。考虑到 CLU 在这些领域中的新兴作用，它也适用于 AD，也适用于中风和乳腺癌。