Catecholaminergic Signaling in Normal Cognition, Aging and Models of Alzheimer's Disease
正常认知、衰老和阿尔茨海默病模型中的儿茶酚胺能信号传导
基本信息
- 批准号:10121456
- 负责人:
- 金额:$ 250.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-15 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:Adrenergic AgentsAdrenergic ReceptorAffectAgingAgonistAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAnimal ModelBehavioral ParadigmBrainBrain StemCell NucleusCognitionCognitiveComplementDataDementiaDiseaseDopamineDorsalEpisodic memoryExhibitsFunctional disorderGeneticGoalsHippocampus (Brain)Impaired cognitionImpairmentIncidenceLeadLearningLevodopaMemoryMemory impairmentMicrotubule-Associated ProteinsModern MedicineMolecularMusMutant Strains MiceNeocortexNeurodegenerative DisordersNeuromodulatorNeuronsNorepinephrinePathologyPharmaceutical PreparationsPharmacologyPhasePlayPopulationProcessRetrievalRisk FactorsRodentRoleSerotoninShort-Term MemorySignal TransductionSourceSymptomsSystemTestingTimeTrainingVentral Tegmental AreaWild Type Mouseagedcell typecognitive benefitsdopaminergic neurongenetic approachgenetic manipulationhippocampal pyramidal neuronhyperphosphorylated tauimprovedlocus ceruleus structurememory encodingmemory processmemory recallmemory retrievalmouse modelneuropathologyneuroregulationnormal agingnovelnovel strategiesnovel therapeuticsreceptorrestorationtau Proteins
项目摘要
SUMMARY
Alzheimer’s disease (AD) and other dementias are a substantial and rapidly growing societal burden due to the
aging of our population. This aging has occurred in part because modern medicine has identified risk factors
and treatments for many other diseases, but not for AD. Thus there is a great and unmet need to do so. A
hallmark symptom of AD and aging without dementia is impaired memory, including retrieval. Further, some of
the earliest neuropathology found in AD is within the systems that provide the neuromodulators dopamine (DA)
and norepinephrine (NE) to the brain (including the hippocampus, a center for declarative/episodic memory).
The largest brainstem adrenergic nucleus is the locus coeruleus (LC), which supplies all of the NE and a
substantial portion of the DA found in the dorsal hippocampus. The LC can also be affected in normal aging.
As such, the goal of this proposal is to better understand the roles and mechanisms by which LC-derived DA
and NE modulate the encoding and retrieval of declarative/episodic memory. Toward this goal, pharmacologic
and genetic manipulations will be performed in rodents, for which there are excellent behavioral paradigms that
rely on hippocampus-dependent memory. Our preliminary studies indicate that all three -adrenergic receptors
that are activated by NE play a critical role in the hippocampus to promote memory retrieval. They also suggest
that adrenergic DA is required for hippocampus-dependent memory. Thus the first aim will examine the
molecular and cellular mechanisms by which -adrenergic receptors promote hippocampus-dependent memory
using combined pharmacologic and genetic approaches. Subcellular localization of receptors in the
hippocampus will also be determined. The second aim will examine the modulation of hippocampus-dependent
memory by “adrenergic” DA using combined pharmacologic and genetic approaches. The third aim will examine
the ability of drugs that enhance DA and NE signaling to promote memory in models of AD and aging. The
completion of these aims will provide a better understanding of how memory encoding and retrieval is facilitated
within the hippocampus, and ultimately may suggest potential targets for enhancing memory in AD and aging.
概括
阿尔茨海默病 (AD) 和其他痴呆症是一个巨大且快速增长的社会负担,原因是
我们的人口老龄化。这种衰老的发生部分是因为现代医学已经确定了危险因素
以及许多其他疾病的治疗方法,但不适用于 AD。因此,这样做的需求巨大且尚未得到满足。一个
AD 和不伴有痴呆的衰老的标志性症状是记忆力受损,包括检索。此外,一些
AD 中最早发现的神经病理学是在提供神经调节剂多巴胺 (DA) 的系统中
去甲肾上腺素 (NE) 进入大脑(包括海马体,陈述性/情景记忆的中心)。
最大的脑干肾上腺素能核是蓝斑 (LC),它提供所有的 NE 和
大部分 DA 存在于背侧海马体中。正常老化过程中,LC 也会受到影响。
因此,本提案的目标是更好地理解 LC 衍生 DA 的作用和机制
NE 调节陈述性/情景记忆的编码和检索。为实现这一目标,药理学
基因操作将在啮齿类动物中进行,对于啮齿类动物来说,有很好的行为范式
依赖于海马体的记忆。我们的初步研究表明所有三种 -肾上腺素能受体
被 NE 激活的神经元在海马体中对于促进记忆提取起着至关重要的作用。他们还建议
海马依赖性记忆需要肾上腺素能 DA。因此第一个目标将检查
-肾上腺素能受体促进海马依赖性记忆的分子和细胞机制
使用药理学和遗传学相结合的方法。 受体的亚细胞定位
海马体也将被确定。第二个目标将检查海马依赖性的调节
使用药理学和遗传学相结合的方法,通过“肾上腺素能”DA 进行记忆。第三个目标将审查
增强 DA 和 NE 信号传导的药物在 AD 和衰老模型中促进记忆的能力。这
完成这些目标将有助于更好地理解如何促进记忆编码和检索
在海马体内,最终可能会提出增强 AD 和衰老记忆的潜在目标。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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{{ truncateString('STEVEN A THOMAS', 18)}}的其他基金
Norepinephrine: A Novel Regulator of Amyloid Beta-42 Peptides
去甲肾上腺素:淀粉样蛋白 Beta-42 肽的新型调节剂
- 批准号:
9761419 - 财政年份:2018
- 资助金额:
$ 250.61万 - 项目类别:
Inducible recombination and gene expression in specific neurotransmitter systems
特定神经递质系统中的诱导重组和基因表达
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8225329 - 财政年份:2008
- 资助金额:
$ 250.61万 - 项目类别:
Inducible recombination and gene expression in specific neurotransmitter systems
特定神经递质系统中的诱导重组和基因表达
- 批准号:
8024532 - 财政年份:2008
- 资助金额:
$ 250.61万 - 项目类别:
Inducible recombination and gene expression in specific neurotransmitter systems
特定神经递质系统中的诱导重组和基因表达
- 批准号:
7778821 - 财政年份:2008
- 资助金额:
$ 250.61万 - 项目类别:
Inducible recombination and gene expression in specific neurotransmitter systems
特定神经递质系统中的诱导重组和基因表达
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7637454 - 财政年份:2008
- 资助金额:
$ 250.61万 - 项目类别:
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6873733 - 财政年份:2002
- 资助金额:
$ 250.61万 - 项目类别:
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