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：
9147489
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/9147489
关键词：
APP-PS1 Abeta clearance Adult Affect Affinity Age-Months Alleles Alzheimer&apos s Disease 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 Breeding 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 Pathology Pathway interactions Patients Pharmacology Population Proteins Publishing Role Senile Plaques Smooth Muscle Myocytes Staging Stroke Testing Therapeutic Toxic effect Transgenic Mice Variant Vascular Diseases Viral abeta deposition amyloid pathology astrogliosis brain parenchyma brain tissue capillary cerebrovascular extracellular genetic risk factor genetic variant genome wide association study 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（由适用提供）：阿尔茨海默氏病（AD）是痴呆症的最常见原因，其特征是细胞外斑块由淀粉样蛋白β（Aβ）胡椒和细胞内缠结形成，由tau蛋白的磷酸化形式组成。 AD中的另一个常见病理是脑淀粉样血管病（CAA），是由Aβ沉积在大脑血管壁中引起的，导致血管功能障碍和出血。 AD和CAA的强遗传危险因素是载脂蛋白E（APOE）基因的ε4等位基因，但是近期全基因组关联研究证明，类似的载脂蛋白簇（Clu）也赋予了AD风险。 CLU在CAA中的作用尚不清楚，但我们有强有力的证据表明CLU与CAA的形成非常重要。尽管对APOE受体生物学知之甚少，但唯一已知的CLU受体LRP2/Megalin在成人大脑中表达的表达很差，这表明存在其他受体，但未被发现。我们发现plexin A4（PLXNA4）是一种新型受体，可调节小鼠和人类中细胞外CLU的水平。与对照组相比，与对照组相比，AD和人AD脑组织的小鼠模型以及人类AD脑组织的PLXNA4水平显着提高。该提议的目的是定义CLU如何调节脑实质和脑血管系统中的Aβ代谢和沉积。使用细胞培养，生物化学，小鼠遗传学，药理学和病理定义的人体组织的结合，我们将通过研究功能性终点，例如组织病理学，血管功能障碍，神经质功能障碍，神经性疾病，电生理学和行为来确定CLU和PLXNA4如何影响AD。鉴于Clu在这些相对领域的新兴作用，解读这一途径不仅可能导致新的AD治疗靶标，而且还可能导致中风和乳腺癌。