Secreted Alzheimer amyloid precursor protein (sAPP) antagonizes Reelin receptors

描述(申请人提供)：淀粉样前体蛋白(APP)通过遗传学、病理学和生物化学与阿尔茨海默病有关。这种蛋白质的一种分泌形式Sappa可以抑制一种名为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-末端；分泌酶(Sapp)产生的分泌形式在C-末端不同，神经调节活性大大减弱。这些生物活性的差异表明与细胞表面受体结合的不同(S)。初步结果表明，Sappa的生物活性是通过与载脂蛋白E受体2(apoE-R2；又名：apoE-R2)结合介导的。LRP8)，已知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的同源二聚化，促进对记忆至关重要的NMDA-R活性。Sappa在低浓度下以单体形式存在，可以想象在不影响其二聚化的情况下与这两种受体中的一种或两种结合。推测Sappa的神经调节作用是通过与LRP8和/或极低密度脂蛋白受体分子单价结合，抑制受体(S)的S二聚体和信号传导而实现的。当Sappa在较高浓度下均二聚时，这种作用可能会消失。这一假设的关键组成部分将通过两个主要目标的实现来检验。首先，将通过在异位细胞类型中强制表达这些受体来测试Sappa与LRP8和VLDL-R的结合。其次，将通过减少它们在哺乳动物神经元中的表达来研究LRP8和VLDL-R在Sappa神经调节活性中的作用。除了为Sappa的基础生物学提供关键的机制见解外，该项目还将促进未来的研究，探索更广泛的假设，重点是其他LRP配体的二聚化潜力，如载脂蛋白E。 与公共健康相关：最直接的是，这项研究的结果将影响有关淀粉样前体蛋白(APP)功能的假设，该蛋白可能在阿尔茨海默病以及在脑瘫和唐氏综合症等人类疾病中受到影响的正常大脑发育方面发挥作用。该项目的发现还将扩展为关于APP与载脂蛋白E(ApoE)相互作用的更大假说，重点放在阿尔茨海默病上，APP和ApoE的基因变异都有助于疾病病因。

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.