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

基本信息

  • 批准号:
    7895211
  • 负责人:
  • 金额:
    $ 15.41万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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(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相关。这种蛋白质的分泌形式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独特的C末端;由â-分泌酶(sAPP â)产生的â APP的分泌形式在C末端不同,并且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差异。初步结果表明sAPPa的生物活性是通过与ApoE受体2(apoE-R2; a.k.a. LRP 8),已知是另一种神经调节蛋白Reelin的受体。Reelin通过引发LRP 8或称为VLDL-R的密切相关受体的同源二聚化来促进对记忆至关重要的NMDA-R活性。sAPPa以低浓度的单体存在,可以设想结合这些受体中的一种或两种而不影响它们的二聚化。在此假设sAPPa的神经调节活性是由单核苷酸结合LRP 8和/或VLDL-R分子介导的,抑制受体的二聚化和信号传导。当sAPPa在更高浓度下均二聚化时,这种效果可能会丧失。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,将通过这些受体在异位细胞类型中的强制表达来测试sAPPa与LRP 8和VLDL-R的结合。第二,LRP 8和VLDL-R在sAPPa的神经调节活性中的作用将通过减少它们在哺乳动物神经元中的表达来检查。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(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关于淀粉样前体蛋白(APP)功能的假设,APP可能在阿尔茨海默病以及在人类条件下受损的正常大脑发育方面发挥作用,如脑瘫和唐氏综合征。该项目的研究结果也将扩展到一个更大的假设,即APP与载脂蛋白E(ApoE)的相互作用,更强调阿尔茨海默病,APP和ApoE的遗传变异有助于疾病病因。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Steven W Barger其他文献

Vascular consequences of passive Aβ immunization for Alzheimer's disease. Is avoidance of "malactivation" of microglia enough?
  • DOI:
    10.1186/1742-2094-2-2
  • 发表时间:
    2005-01-11
  • 期刊:
  • 影响因子:
    10.100
  • 作者:
    Steven W Barger
  • 通讯作者:
    Steven W Barger
Induction of serine racemase expression and D-serine release from microglia by amyloid β-peptide
  • DOI:
    10.1186/1742-2094-1-2
  • 发表时间:
    2004-01-01
  • 期刊:
  • 影响因子:
    10.100
  • 作者:
    Sheng-Zhou Wu;Angela M Bodles;Mandy M Porter;W Sue T Griffin;Anthony S Basile;Steven W Barger
  • 通讯作者:
    Steven W Barger
Unique aspects of transcriptional regulation in neurons – nuances in NFκB and Sp1-related factors
  • DOI:
    10.1186/1742-2094-6-16
  • 发表时间:
    2009-01-01
  • 期刊:
  • 影响因子:
    10.100
  • 作者:
    Xianrong R Mao;Andréa M Moerman-Herzog;Yuzhi Chen;Steven W Barger
  • 通讯作者:
    Steven W Barger

Steven W Barger的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Steven W Barger', 18)}}的其他基金

Role of glucose transport in Alzheimer's disease pathogenesis
葡萄糖转运在阿尔茨海默病发病机制中的作用
  • 批准号:
    10768392
  • 财政年份:
    2023
  • 资助金额:
    $ 15.41万
  • 项目类别:
Compromised function of a glial glucose transporter in aging and Alzheimer's disease
衰老和阿尔茨海默病中神经胶质葡萄糖转运蛋白的功能受损
  • 批准号:
    10542429
  • 财政年份:
    2021
  • 资助金额:
    $ 15.41万
  • 项目类别:
Compromised function of a glial glucose transporter in aging and Alzheimer's disease
衰老和阿尔茨海默病中神经胶质葡萄糖转运蛋白的功能受损
  • 批准号:
    10762675
  • 财政年份:
    2021
  • 资助金额:
    $ 15.41万
  • 项目类别:
Compromised function of a glial glucose transporter in aging and Alzheimer's disease
衰老和阿尔茨海默病中神经胶质葡萄糖转运蛋白的功能受损
  • 批准号:
    10610184
  • 财政年份:
    2021
  • 资助金额:
    $ 15.41万
  • 项目类别:
Compromised function of a glial glucose transporter in aging and Alzheimer's disease
衰老和阿尔茨海默病中神经胶质葡萄糖转运蛋白的功能受损
  • 批准号:
    10194855
  • 财政年份:
    2021
  • 资助金额:
    $ 15.41万
  • 项目类别:
Compromised function of a glial glucose transporter in aging and Alzheimer's disease
衰老和阿尔茨海默病中神经胶质葡萄糖转运蛋白的功能受损
  • 批准号:
    10393048
  • 财政年份:
    2021
  • 资助金额:
    $ 15.41万
  • 项目类别:
Destablization of LRP family receptors by Alzheimer-related presenilin mutations
阿尔茨海默病相关早老素突变导致 LRP 家族受体不稳定
  • 批准号:
    8741904
  • 财政年份:
    2013
  • 资助金额:
    $ 15.41万
  • 项目类别:
Destablization of LRP family receptors by Alzheimer-related presenilin mutations
阿尔茨海默病相关早老素突变导致 LRP 家族受体不稳定
  • 批准号:
    8635877
  • 财政年份:
    2013
  • 资助金额:
    $ 15.41万
  • 项目类别:
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:
    8078060
  • 财政年份:
    2010
  • 资助金额:
    $ 15.41万
  • 项目类别:
Sp1, kappa-B enhancers and transcriptions in neurons
Sp1、kappa-B 增强子和神经元中的转录
  • 批准号:
    7340511
  • 财政年份:
    2004
  • 资助金额:
    $ 15.41万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了