Glutamate neurotransmission in Alzheimer's disease progression
阿尔茨海默病进展中的谷氨酸神经传递
基本信息
- 批准号:10398111
- 负责人:
- 金额:$ 58.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-15 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:APP-PS1AcuteAddressAffectAgeAge-MonthsAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAmyloid beta-42Amyloid beta-ProteinAnimalsAxonBehavioralBrainChronicCognitionCognitiveDementiaDiseaseDisease ProgressionEarly identificationElectrochemistryEvaluationEventFunctional disorderGlutamate TransporterGlutamatesHippocampus (Brain)HumanImmunohistochemistryImpaired cognitionImpairmentInterventionKineticsKnock-inKnock-in MouseKnowledgeLeadLearningLong-Term DepressionMeasurementMeasuresMemoryMemory LossMemory impairmentMessenger RNAMetabolicMusNerve DegenerationNeurobiologyNeurogliaOxidative StressPathologicPathway interactionsPatientsPharmacologyPhasePlayProtein AnalysisProtein IsoformsProteinsResearchResolutionRoleSenile PlaquesSiteStimulusSymptomsSynapsesSystemTechniquesTestingTherapeuticTimeTissuesTransgenic Organismsabeta accumulationalpha Bungarotoxinawakebiomarker identificationcognitive testingcohortearly detection biomarkersexcitotoxicityexperimental studyextracellularhyperphosphorylated tauimprovedin vivoinsightmemory recallmild cognitive impairmentmillisecondmitochondrial dysfunctionmorris water mazemouse modelneuroinflammationneuropathologyneuroregulationneurotoxicneurotransmissionnew therapeutic targetnovelobject recognitionoptimal treatmentspostsynapticpre-clinicalpresynapticpresynaptic neuronspreventive interventiontau Proteinstherapeutic targetuptakevesicular glutamate transporter 1
项目摘要
Project Summary/Abstract
In spite of the evidence supporting the involvement of the glutamatergic system in Alzheimer’s
disease (AD), research has focused on indirect measures of glutamate (Glu) involvement, mainly
through increased downstream pathways related to excitotoxicity, without addressing possible
changes in extracellular Glu occurring during disease progression. Knowledge of basal and
phasic extracellular Glu levels and clearance kinetics would allow us to establish an early
biomarker, better determine and explore novel therapeutic targets, and establish the opportune
treatment window that has the potential to alter AD progression. Until recently, research
measuring extracellular Glu levels has been limited because few techniques are capable of in
vivo analysis within small sub-regions of the brain. We have developed a MEA that, when
combined with electrochemistry, has the ability to measure micromolar changes in basal and
phasic extracellular Glu with high temporal (msec) and spatial (micron) resolution during acute
and chronic recordings. We plan to use this technique to address our central hypothesis that
alterations in extracellular Glu in awake animals occur prior to cognitive decline and
neuropathology associated with AD, and that Aβ accumulation with age potentiates these
changes resulting in the cognitive decline typical in AD. This hypothesis will be evaluated using
a novel knock-in mouse model of AD, APPNL-F/NL-F mice, and APP/PS1 mice, and their respective
controls at 2-4, 8-10, and 18-20 months of age. At these ages, one cohort of mice will undergo
cognitive evaluation using the Morris water maze followed by awake stimulus (KCl)-evoked Glu
recordings in the CA1 region of the hippocampus. These studies will help us determine if basal
Glu and Glu release (presynaptic) and uptake (glia and postsynaptic) kinetics are altered in AD
mice and if so, how and when these alterations occur over the continuum of cognitive and
pathophysiological decline. Next, to determine if alterations in Glu neurotransmission is
behaviorally detrimental, we will examine a second group of mice at the same ages and
hippocampal sub-region during a memory related task, the spontaneous alternation y maze. This
will allow us to determine the impact of aging and AD progression on formation and recall of
memories in the form of phasic Glu measurements. Taken together, we anticipate that these
studies will give us valuable insight into the role of Glu as an early biomarker, a mechanism for
disease progression, a site for potential novel therapeutic targets, and optimal intervention
timeframes for AD.
项目总结/摘要
尽管有证据支持阿尔茨海默氏症与多巴胺能系统有关,
疾病(AD),研究主要集中在谷氨酸(Glu)参与的间接措施,主要是
通过增加与兴奋性毒性相关的下游途径,而没有解决可能的
在疾病进展期间发生的细胞外Glu的变化。基础知识和
阶段性细胞外Glu水平和清除动力学将使我们能够建立早期的
生物标志物,更好地确定和探索新的治疗靶点,并建立合适的
可能改变AD进展的治疗窗。直到最近,研究
测量细胞外Glu水平受到限制,因为很少有技术能够在
在大脑的小分区内进行体内分析。我们制定了一项多边环境协定,
结合电化学,有能力测量微摩尔变化的基础和
在急性期具有高时间(毫秒)和空间(微米)分辨率的时相细胞外Glu
和慢性记录。我们计划使用这种技术来解决我们的中心假设,
在清醒的动物中细胞外Glu的改变发生在认知下降之前,
与AD相关的神经病理学,并且随着年龄的增长,Aβ的积累增强了这些
导致AD中典型的认知下降的变化。该假设将使用
一种新的AD敲入小鼠模型,APPNL-F/NL-F小鼠和APP/PS1小鼠,以及它们各自的
2-4、8-10和18-20月龄的对照。在这些年龄,一组小鼠将经历
使用Morris水迷宫进行认知评估,随后使用清醒刺激(KCl)诱发的Glu
在海马CA 1区的记录。这些研究将帮助我们确定基础
在AD中Glu和Glu释放(突触前)和摄取(神经胶质和突触后)动力学改变
小鼠,如果是这样,这些变化如何以及何时发生在认知和
病理生理衰退接下来,为了确定Glu神经传递的改变是否是
行为有害,我们将检查第二组相同年龄的小鼠,
海马亚区在记忆相关的任务,自发交替y迷宫。这
将使我们能够确定衰老和AD进展对大脑皮层的形成和回忆的影响。
以阶段性Glu测量的形式存储。综上所述,我们预计,
研究将使我们有价值地了解谷氨酸作为早期生物标志物的作用,
疾病进展、潜在新治疗靶点和最佳干预
AD的时间表。
项目成果
期刊论文数量(24)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Sex-Dependent Effects of Chronic Circadian Disruption in AβPP/PS1 Mice.
AβPP/PS1 小鼠慢性昼夜节律紊乱的性别依赖性影响。
- DOI:10.3233/jad-230089
- 发表时间:2024
- 期刊:
- 影响因子:0
- 作者:Britz,Jesse;Ojo,Emmanuel;Haque,Nazmul;Dhukhwa,Asmita;Hascup,ErinR;Hascup,KevinN;Tischkau,ShelleyA
- 通讯作者:Tischkau,ShelleyA
Prodromal Glutamatergic Modulation with Riluzole Impacts Glucose Homeostasis and Spatial Cognition in Alzheimer's Disease Mice.
- DOI:10.3233/jad-221245
- 发表时间:2023
- 期刊:
- 影响因子:4
- 作者:Findley, Caleigh A.;McFadden, Samuel A.;Cox, MaKayla F.;Sime, Lindsey N.;Peck, Mackenzie R.;Quinn, Kathleen;Bartke, Andrzej;Hascup, Kevin N.;Hascup, Erin R.
- 通讯作者:Hascup, Erin R.
Relationships among Development, Growth, Body Size, Reproduction, Aging, and Longevity - Trade-Offs and Pace-Of-Life.
- DOI:10.1134/s0006297923110020
- 发表时间:2023-11
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Sexual dimorphic metabolic and cognitive responses of C57BL/6 mice to Fisetin or Dasatinib and quercetin cocktail oral treatment.
- DOI:10.1007/s11357-023-00843-0
- 发表时间:2023-10
- 期刊:
- 影响因子:5.6
- 作者:Fang, Yimin;Medina, David;Stockwell, Robert;McFadden, Sam;Quinn, Kathleen;Peck, Mackenzie R.;Bartke, Andrzej;Hascup, Kevin N.;Hascup, Erin R.
- 通讯作者:Hascup, Erin R.
Responses to Many Anti-Aging Interventions Are Sexually Dimorphic.
- DOI:10.5534/wjmh.230015
- 发表时间:2024-01
- 期刊:
- 影响因子:0
- 作者:Bartke A;Hascup E;Hascup K
- 通讯作者:Hascup K
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Erin R Hascup其他文献
Erin R Hascup的其他文献
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{{ truncateString('Erin R Hascup', 18)}}的其他基金
Cellular senescence, inflammation and neurotransmission in Alzheimer's disease
阿尔茨海默病中的细胞衰老、炎症和神经传递
- 批准号:
9788263 - 财政年份:2018
- 资助金额:
$ 58.31万 - 项目类别:
Cellular senescence, inflammation and neurotransmission in Alzheimer's disease
阿尔茨海默病中的细胞衰老、炎症和神经传递
- 批准号:
10450727 - 财政年份:2018
- 资助金额:
$ 58.31万 - 项目类别:
Cellular senescence, inflammation and neurotransmission in Alzheimer's disease
阿尔茨海默病中的细胞衰老、炎症和神经传递
- 批准号:
10198750 - 财政年份:2018
- 资助金额:
$ 58.31万 - 项目类别:
Glutamate neurotransmission in Alzheimer's disease progression
阿尔茨海默病进展中的谷氨酸神经传递
- 批准号:
9906833 - 财政年份:2018
- 资助金额:
$ 58.31万 - 项目类别:
Research Supplement to Promote Diversity for R01AG061937
促进 R01AG061937 多样性的研究补充
- 批准号:
9924186 - 财政年份:2018
- 资助金额:
$ 58.31万 - 项目类别:
Equipment request to increase scientific rigor and reproducibility
提高科学严谨性和可重复性的设备要求
- 批准号:
10060295 - 财政年份:2018
- 资助金额:
$ 58.31万 - 项目类别:
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