The role of Clusterin in cerebral amyloid angiopathy

 描述（由申请人提供）：阿尔茨海默病（AD）是痴呆症的最常见病因，其特征在于淀粉样蛋白-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的另一种常见病理是脑淀粉样血管病（CAA），由脑血管壁中的Aβ沉积引起，导致血管功能障碍和出血。AD和CAA的最强遗传风险因素是载脂蛋白E（APOE）基因的ε4等位基因，但最近的多项全基因组关联研究证明，类似的载脂蛋白，胆固醇（CLU），也赋予AD的风险。CLU在CAA中的作用尚不清楚，但我们有强有力的证据表明CLU在CAA的形成中起着关键作用。虽然对apoE受体生物学了解很多，但Clu唯一已知的受体LRP 2/Megalin在成人大脑中表达非常差，这表明其他受体存在但未被发现。我们已经发现丛蛋白A4（PLXNA 4）是一种新型受体，其调节小鼠和人类细胞外CLU的水平。与对照相比，在AD小鼠模型以及人AD脑组织中PLXNA 4水平显著降低。本研究的目的是明确CLU如何调节Aβ在脑实质和脑血管中的代谢和沉积。使用细胞培养，生物化学，小鼠遗传学，药理学和病理学定义的人体组织的组合，我们将确定CLU和PLXNA 4如何影响AD通过研究功能终点，如组织病理学，血管功能障碍，神经炎性营养不良，电生理学和行为。破译这一途径不仅可以为AD，而且还可以为中风和乳腺癌提供新的治疗靶点，因为CLU在这些领域中的作用正在显现。

 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.