Secreted Alzheimer amyloid precursor protein (sAPP) antagonizes Reelin receptors

分泌型阿尔茨海默淀粉样前体蛋白 (sAPP) 拮抗 Reelin 受体

• 批准号: 7895211
• 负责人: Steven W Barger
• 金额: $ 15.41万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895211
• 关键词: Affinity; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Apolipoprotein E; Binding; Biochemistry; Biological; Biological Assay; Biology; Brain; Calcium; Cell Surface Receptors; Cell Survival; Cerebral Palsy; Dependency; Development; Dimerization; Disease; Down Syndrome; Equilibrium; Etiology; Event; Future; Genetic; Genetic Variation; Hippocampus (Brain); Homodimerization; Human; Kinetics; LDL-Receptor Related Protein 1; Ligands; Mediating; Memory; N-Methyl-D-Aspartate Receptors; Neurons; Neurotransmitter Receptor; Oligonucleotides; Pathology; Physiological; Play; Proteins; Role; Signal Transduction; Small Interfering RNA; Specificity; Testing; VLDL receptor; apolipoprotein E-2; cell type; dimer; insight; monomer; mutant; neuroregulation; public health relevance; receptor; receptor binding; receptor expression; reelin protein; reelin receptor; secretase

DESCRIPTION (provided by applicant): The ¿-amyloid precursor protein (¿APP) is connected to Alzheimer's disease by genetics, pathology, and biochemistry. A secreted form of this protein, sAPPa, can inhibit the activity of a class of neurotransmitter receptor called the NMDA receptor. This "neuromodulation" requires the unique C-terminus of sAPPa; the secreted form of ¿APP produced by ¿-secretase (sAPP¿) differs at the C-terminus and is much diminished in neuromodulatory activity. These differences in bioactivity suggest differences in binding to cell-surface receptor(s). Preliminary results suggests that the bioactivity of sAPPa is mediated by binding to the ApoE receptor 2 (apoE-R2; a.k.a. LRP8), known to be a receptor for another neuromodulatory protein, Reelin. Reelin facilitates NMDA-R activity critical for memory by eliciting homodimerization of LRP8 or a closely related receptor termed VLDL-R. Existing as a monomer at low concentrations, sAPPa could be envisioned to bind one or both of these receptors without effecting their dimerization. It is hypothesized here that the neuromodulatory activity of sAPPa is mediated by monovalently binding a LRP8 and/or VLDL-R molecule, inhibiting the receptor(s)'s dimerization and signaling. This effect may be lost as sAPPa homodimerizes at higher concentrations. Key components of this hypothesis will be tested by accomplishment of two main objectives. First, the binding of sAPPa to LRP8 and VLDL-R will be tested by forced expression of these receptors in an ectopic cell type. Second, the role of LRP8 and VLDL-R in the neuromodulatory activity of sAPPa will be examined by reducing their expression in mammalian neurons. In addition to providing key mechanistic insights into the basic biology of sAPPa, this project will facilitate future studies exploring a broader hypothesis that focuses on the dimerization potential of other LRP ligands such as apolipoprotein E. PUBLIC HEALTH RELEVANCE: Most immediately, the results of this study will influence hypotheses about the function of the ¿-amyloid precursor protein (¿APP), which may play a role in Alzheimer's disease as well as aspects of normal brain development that are compromised in human conditions such as cerebral palsy and Down's syndrome. The findings from this project will also be expanded into a larger hypothesis concerning the interactions of ¿APP with apolipoprotein E (ApoE), with greater emphasis on Alzheimer's disease, where genetic variations in both ¿APP and ApoE contribute to disease etiology.

描述（由申请人提供）： ¿ -淀粉样蛋白前体蛋白 (¿APP) 通过遗传学、病理学和生物化学与阿尔茨海默病相关。这种蛋白的分泌形式 sAPPa 可以抑制一类称为 NMDA 受体的神经递质受体的活性。这种“神经调节”需要。 sAPPa 的独特 C 末端；¿ APP制作者 ¿ -分泌酶 (sAPP?) 在 C 末端有所不同，并且神经调节活性大大减弱。这些生物活性差异表明与细胞表面受体的结合存在差异。初步结果表明 sAPPa 的生物活性是通过与细胞表面受体的结合介导的。 ApoE 受体 2（apoE-R2；又名 LRP8），已知是另一种神经调节蛋白 Reelin 的受体。 NMDA-R 活性通过引发 LRP8 或称为 VLDL-R 的密切相关受体的同二聚化而对记忆至关重要。sAPPa 可以在低浓度下以单体形式结合这些受体中的一种或两种，而不影响它们的二聚化。 sAPPa 的神经调节活性是通过单价结合 LRP8 和/或 VLDL-R 分子介导的，抑制受体的二聚化当 sAPPa 在较高浓度下同源二聚化时，这种效应可能会消失，这一假设的关键成分将通过两个主要目标的实现进行测试，首先，将通过这些物质的强制表达来测试 sAPPa 与 LRP8 和 VLDL-R 的结合。其次，除了提供关键机制外，还将通过减少它们在哺乳动物神经元中的表达来检查 LRP8 和 VLDL-R 在 sAPPa 神经调节活性中的作用。通过深入了解 sAPPa 的基本生物学，该项目将促进未来的研究探索更广泛的假设，重点关注其他 LRP 配体（如载脂蛋白 E）的二聚化潜力。 公共卫生相关性：最直接的是，这项研究的结果将影响有关 ¿ 功能的假设。 -淀粉样前体蛋白（¿APP），它可能在阿尔茨海默氏病以及脑瘫和唐氏综合症等人类疾病中受损的正常大脑发育方面发挥作用。关于 ¿ 相互作用的更大假设APP 与载脂蛋白 E (ApoE)，更强调阿尔茨海默氏病，其中两种疾病的遗传变异 ¿ APP 和 ApoE 有助于疾病病因学。