Role of Fibulin-1 in APP Processing

Fibulin-1 在 APP 处理中的作用

• 批准号: 8581789
• 负责人: KELLEY M ARGRAVES
• 金额: $ 22.43万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8581789
• 关键词: Abeta synthesis; Address; Alkaline Phosphatase; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Behavior; Binding; Brain; Cells; Cognitive; Conditioned Culture Media; Dementia; Development; Disintegrins; Embryo; Engineering; Enzymes; Epidermal Growth Factor; Etiology; Event; Extracellular Matrix Proteins; Family; Fibroblasts; Functional disorder; Gene Deletion; Goals; Heparin Binding; Knockout Mice; Lead; Mediating; Membrane; Metalloproteases; Mus; Neuregulin 1; Neuroblastoma; Neurodegenerative Disorders; Neurons; Pathogenesis; Peptides; Phorbol Esters; Play; Process; Production; Proteolysis; Proteolytic Processing; Role; Senile Plaques; Small Interfering RNA; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; Transgenic Organisms; alpha secretase; amyloid precursor protein processing; base; beta secretase; brain cell; cellular engineering; combat; fibulin 1; gamma secretase; inhibitor/antagonist; interest; member; overexpression; public health relevance; secretase; therapeutic target

DESCRIPTION (provided by applicant): Many current pharmacological approaches to combating Alzheimer's disease (AD) seek to block Abeta production through inhibition of the amyloidogenic enzymes known as beta- and gamma-secretases. An alternative approach is to activate the alpha-secretase processing of amyloid precursor protein (APP), which is mediated by several members of the disintegrin family of metalloproteases, ADAM9, ADAM10 and ADAM17. Processing of APP by these alpha-secretases is thought to be beneficial with respect to AD since it limits production of Abeta and generates the neuroprotective soluble APPalpha (sAPPalpha) product. Fibulin-1 (Fbln1) is an extracellular matrix protein, expressed in the brain by neurons, that binds the amino terminus of APP and sAPPalpha. The significance of this interaction is not yet established however, we have found that Fbln1 also binds to other membrane anchored alpha-secretase substrates, heparin binding-epidermal growth factor (HB-EGF) and neuregulin-1 (NRG1). We also show that Fbln1 acts to inhibit the proteolytic release of soluble forms of HB-EGF and NRG1. Furthermore, we have found increased levels of sAPPalpha in the conditioned culture medium of Fbln1 null mouse embryo fibroblasts (MEFs) as compared to wildtype MEFs. Based on these findings it is hypothesized that Fbln1 serves as an inhibitor of alpha-secretase processing of APP and therefore may represent a therapeutic target that if inhibited might lead to augmented alpha-secretase processing of APP and reduced pathological APP cleavage. To address this hypothesis there are three specific aims: 1) Determine whether brain APP proteolytic cleavage is altered in Fbln1-deficient mice, 2) determine whether transgenic overexpression of Fbln1 accelerates Abeta production and exacerbates AD pathogenesis, and 3) determine whether Fbln1 inhibits alpha-secretase processing of APP in cultured neuronal cells.

描述（由申请人提供）：对抗阿尔茨海默氏病（AD）的许多当前药理方法试图通过抑制称为β-和γ-分泌酶的淀粉样蛋白酶生成酶来阻止Abeta产生。另一种方法是激活淀粉样蛋白前体蛋白（APP）的α-分泌酶加工，该加工是由金属蛋白酶的分解蛋白家族ADAM9，ADAM9，ADAM10和ADAM17介导的。这些α-分泌酶对APP的处理在AD方面被认为是有益的，因为它限制了Abeta的产生并生成神经保护性可溶性appalpha（Sappalpha）产品。 Fibulin-1（FBLN1）是一种细胞外基质蛋白，通过神经元在大脑中表达，它结合了App和Sappalpha的氨基末端。但是，尚未确定这种相互作用的重要性，我们发现FBLN1还与其他膜锚定α-分泌酶底物，肝素结合 - 表皮生长因子（HB-EGF）和Neuregulin-1（NRG1）结合。我们还表明，FBLN1的作用是抑制HB-EGF和NRG1可溶性形式的蛋白水解释放。此外，与WildType MEF相比，我们发现在FBLN1 NULL小鼠胚胎成纤维细胞（MEF）的条件培养基中，sappalpha的水平增加。基于这些发现，假设FBLN1是APP的α-分泌酶处理的抑制剂，因此可能代表了一个治疗靶标，即如果被抑制可能会导致APP的α-分泌酶处理增加并减少病理APP裂解。要解决这一假设，有三个具体的目的：1）确定在FBLN1缺陷型小鼠中是否改变了脑应用蛋白水解裂解，2）确定FBLN1的转基因过表达是否会加速Abeta的产生和加剧AD AD AD AD AD AD AD病原体，3）确定FBLN1是否确定FBLN1是否抑制了Alpha Alpha Alpha Alpha Alpha Alpha iNUDIND ALPHA INPHIS ALPHAININD ALPHA INFLININD ALPHA INPHININD ALPHAINIS AIN FIND FIND FIND FINDIND AIN FIND FINDIND ALPHAIND INDING ALPHA。 - 培养的神经元细胞中APP的分泌酶处理。