Physiologic Mechanisms of Action of APP and APLP2 in Axon Targeting
APP 和 APLP2 在轴突靶向中作用的生理机制
基本信息
- 批准号:8623239
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-15 至 2015-08-31
- 项目状态:已结题
- 来源:
- 关键词:Adverse effectsAfferent NeuronsAlzheimer&aposs DiseaseAmyloidAmyloid beta-Protein PrecursorAnatomyAxonBindingBiochemicalBiological ModelsBrainCell Adhesion MoleculesChondroitin SulfatesClinicalCuesDataDefectDevelopmentExhibitsExtracellular DomainGenesGeneticGrowth ConesHeparan Sulfate ProteoglycanHeparitin SulfateHomologous GeneHomologous ProteinHumanImmunoprecipitationIn VitroInterventionInvestigationKnock-outKnowledgeMaintenanceMammalsMapsMusNeuromuscular JunctionOlfactory EpitheliumOrthologous GenePathogenesisPatientsPeptide HydrolasesPeripheralPhysiologicalPlayProcessProtein FamilyProtein IsoformsProteinsProteoglycanProteomicsPublishingRNA SplicingRelative (related person)ReportingRoleSeriesSorting - Cell MovementSystemTestingTissue EmbeddingTranscriptYeastsadverse outcomeaxon guidancebeta-site APP cleaving enzyme 1contactinin vivoinsightintercellular communicationloss of functionmemberneural circuitnext generation sequencingolfactory bulbpre-clinicalprotein expressionpublic health relevanceresearch studytooltranscriptome sequencing
项目摘要
Abstract
The amyloid precursor protein (APP) is thought to play a central role in the pathogenesis of Alzheimer's
disease. In mammals, APP has two amyloid precursor like protein (APLP) homologs, and the physiological
functions of this family of proteins remain poorly understood. Orthologs of APP are not present in yeast, but are
conserved from worms to humans, suggesting they provide a fundamental role in intercellular communication.
In preliminary data, we demonstrate that mouse lines with genetic deletion of either APP or APLP2 exhibit a
loss of fidelity of axon projections of olfactory sensory neurons (OSNs), indicating an essential role for these
proteins in the establishment and/or maintenance of the precise wiring diagram of the olfactory neural circuit.
Next generation sequencing data derived from isolated OSNs indicates that APLP2 and APP are highly
expressed in OSNs (ranked #26 and #29, respectively, of 27,390 annotated transcripts). We recently published
that loss of function of the BACE1 protease, a key protease that processes proteins of the APP family as well
as many other axon guidance molecules, also leads to connectivity errors in the mouse olfactory neural circuit.
Here, we propose that APP and APLP2 function physiologically in the formation and maintenance of the
precise axon projection map of the mouse olfactory neural circuit. This hypothesis is supported by several
observations from others. APP associates with numerous adhesion molecules as well as proteins with
established roles in axon guidance, such as netrin and contactin 4. Indeed, many of these associated proteins
are expressed in OSNs, too, as evidenced by our next generation sequencing data. Alternatively spliced
extracellular domains of APP and APLP2 can be modified posttranslationally by chondroitin sulfate. This
alternatively spliced APLP2 isoform is expressed at high levels in OSNs. In addition, the extracellular domains
of APP and APLP2 bind heparan sulfate in vitro. Both of these proteoglycans contribute to the environmental
cues that repel or attract growth cones and are present in tissue embedding the olfactory neural circuit. To test
the role of APP and APLP2 to precisely map axon projections, we deploy a combination of genetic tools
developed to manipulate the mouse olfactory circuit to examine the consequences of selective deletion of APP
and/or APLP2 exclusively in OSNs (Aim 1). Furthermore, we take advantage of the high levels of expression of
APP and APLP2 to purify and identify proteins associated with APP and/or APLP2 derived from mouse OSNs
(Aim 2). Together, the knowledge gained from these studies will advance our understanding of the physiologic
function of this important protein family and may provide insight into the pathogenesis of Alzheimer's disease
as well as into adverse consequences of the therapies under development for Alzheimer's disease to alter the
levels of APP and its cleavage products.
摘要
淀粉样前体蛋白(APP)被认为在阿尔茨海默病的发病机制中起核心作用
疾病。在哺乳动物中,APP有两个淀粉样前体蛋白(APLP)同源物,以及生理上的
这一蛋白质家族的功能仍然知之甚少。酵母中不存在APP的直系同源物,但
从蠕虫到人类都是保守的,这表明它们在细胞间的交流中发挥了重要作用。
在初步数据中,我们证明了APP或APLP2基因缺失的小鼠品系表现出
嗅觉感觉神经元(OSN)轴突投射的保真度丧失,表明这些神经元在
蛋白质在建立和/或维持嗅神经回路的精确接线图中起着重要作用。
从分离的OSN获得的下一代测序数据表明,APLP2和APP具有高度的
在OSN中表达(分别在27,390份带注释的成绩单中排名第26和第29)。我们最近发表了
BACE1蛋白酶功能的丧失,这是一种关键的蛋白酶,也处理APP家族的蛋白质
与许多其他轴突引导分子一样,也会导致小鼠嗅觉神经回路的连接错误。
在此,我们认为APP和APLP2在心脏的形成和维持中起着生理作用。
精确的小鼠嗅觉神经回路轴突投影图。这一假设得到了几个人的支持
其他人的观察。APP与大量的黏附分子以及与
在轴突引导中已确定的作用,如Netrin和Conactin 4。事实上,这些相关蛋白中的许多
也在OSN中表达,我们的下一代测序数据证明了这一点。交替拼接
APP和APLP2的胞外区可以被硫酸软骨素翻译后修饰。这
另一种剪接的APLP2亚型在OSN中高水平表达。此外,胞外结构域
APP和APLP2在体外与硫酸乙酰肝素结合。这两种蛋白多糖都对环境有贡献
排斥或吸引生长锥体的线索,存在于嵌入嗅神经回路的组织中。为了测试
APP和APLP2的作用为了精确定位轴突投射,我们部署了一组遗传工具
开发用于操作鼠标嗅觉电路以检查选择性删除APP的后果
和/或仅在OSN中使用APLP2(目标1)。此外,我们利用了高水平的表达
APP和APLP2纯化和鉴定小鼠OSN来源的APP和/或APLP2相关蛋白
(目标2)。总之,从这些研究中获得的知识将促进我们对生理学的理解
这一重要蛋白家族的功能,并可能为阿尔茨海默病的发病机制提供洞察力
以及正在开发的阿尔茨海默病疗法的不良后果,以改变
APP及其切割产物的水平。
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)
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