Secreted Alzheimer amyloid precursor protein (sAPP) antagonizes Reelin receptors

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有关。这种蛋白质的分泌形式sAPPa可以抑制一类被称为NMDA受体的神经递质受体的活性。这种“神经调节”需要sAPPa独特的c端；分泌酶（sAPP）产生的APP的分泌形式在c端不同，神经调节活性大大降低。这些生物活性的差异表明与细胞表面受体结合的差异。初步结果表明，sAPPa的生物活性是通过与ApoE受体2 （ApoE - r2，又名LRP8）结合介导的，而ApoE受体2是另一种神经调节蛋白Reelin的受体。Reelin通过诱导LRP8或一种密切相关的受体VLDL-R的二聚化来促进NMDA-R的活性，这对记忆至关重要。在低浓度下作为单体存在，sAPPa可以结合一个或两个受体而不影响它们的二聚化。这里假设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，从而抑制受体的二聚化和信号传导。当sAPPa在较高浓度下发生同二聚时，这种效应可能会消失。这一假设的关键组成部分将通过实现两个主要目标来检验。首先，sAPPa与LRP8和VLDL-R的结合将通过在异位细胞类型中强迫表达这些受体来测试。其次，LRP8和VLDL-R在sAPPa神经调节活性中的作用将通过降低它们在哺乳动物神经元中的表达来检验。除了为sAPPa的基本生物学提供关键的机制见解外，该项目还将促进未来研究探索其他LRP配体（如载脂蛋白E）二聚化潜力的更广泛假设。

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.