Memory and ProBDNF Processing in the Aged Mouse Hippocampus

老年小鼠海马体的记忆和 ProBDNF 处理

基本信息

批准号：
8113539
负责人：
Mona Buhusi
金额：
$ 18.14万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8113539
关键词：
Acetylcholine Actins Adult Affect Age-associated memory impairment Aging Alteplase Animals Apical Apoptotic Behavioral Biochemical Brain Brain region Brain-Derived Neurotrophic Factor Cells Cleaved cell Cognitive deficits Complex Data Decision Making Dementia Dendrites Dendritic Spines Dorsal Due Process Equilibrium Family Functional disorder Future Health Hippocampus (Brain)Impaired cognition In Vitro Individual Injection of therapeutic agent Label Learning Matrix Metalloproteinases Memory Memory impairment Molecular Molecular Analysis Mus NGFR Protein Nerve Degeneration Nerve Growth Factors Neurites Neurodegenerative Disorders Neuronal Dysfunction Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Oxidative Stress Pathway interactions Peptide Hydrolases Performance Plasmin Plasminogen Plasminogen Activator Inhibitor 1 Play Population Presynaptic Terminals Prevalence Process Proprotein Convertases Proteolytic Processing Radial Role Signal Transduction Spinal Ganglia Staging Subtilisins Synapses Synaptic plasticity Vertebral column Water age related aged aging brain aging hippocampus cholinergic neuron density depolymerization hippocampal pyramidal neuron improved inhibitor/antagonist juvenile animal kexin member memory process neuronal survival neuroprotection neuroserpin neurotransmission neurotrophic factor neurotrophin 4 new therapeutic target normal aging novel pre-clinical prevent receptor small hairpin RNA sortilin synaptogenesis transcriptional coactivator p75

项目摘要

DESCRIPTION (provided by applicant): Aging-associated cognitive decline is a frequent condition among individuals aged 60 and over, with prevalence estimated at 20-27%, and is of high use for the identification of preclinical stages of dementia. Deficits in memory tasks are often related to dysfunctions of the hippocampus and cholinergic neurons projecting to the hippocampus and cortex. While present therapies for neurodegeneration and cognitive deficits are focused on neuroprotection from oxidative stress and supporting acetylcholine neurotransmission, this project proposes a change of paradigm towards proteolytic processing of pro-neurotrophins. The balance between neurotrophins and their precursors regulates critically important processes in developing and adult brains, including neuronal survival, synaptogenesis and synaptic plasticity, and may play important roles in preventing aging-related degeneration. We will study the role of proBDNF in hippocampal neuron dysfunctions underlying aging-related memory impairment using a multilevel approach: behavioral, pharmacological, biochemical and neuroanatomical. We will investigate proBDNF processing in the aged versus young mouse hippocampus, and we will evaluate correlations between BDNF signaling and memory deficits in a behavioral task. We will also pharmacologically manipulate proBDNF processing in order to improve memory performance in aged animals. Should this study be successful, it would impact future therapies aimed at preserving memory performance in aged individuals by identifying a new set of molecular pathways to be targeted by therapy. PUBLIC HEALTH RELEVANCE: Aging-associated cognitive decline is a frequent condition among individuals aged 60 and over, with prevalence estimated at 20-27%, and is of high use for the identification of preclinical stages of dementia. Deficits in memory tasks are often related to dysfunctions of the hippocampus and cholinergic neurons projecting to the hippocampus and cortex. Our studies will investigate a molecular pathway to be targeted by future therapies aimed at preserving memory performance in aged individuals.

描述（由申请人提供）：与衰老相关的认知下降是60岁及以上的个体的常见状况，估计率为20-27％，并且在鉴定痴呆症的临床前阶段有很高的使用。记忆任务中的缺陷通常与投射到海马和皮质的海马和胆碱能神经元的功能障碍有关。尽管现有的神经退行性和认知缺陷的疗法集中于氧化应激和支持乙酰胆碱神经传递的神经保护作用，但该项目提出将范式转换为促尿果蛋白的蛋白水解处理。神经营养蛋白及其前体之间的平衡调节了发展和成年大脑的至关重要的过程，包括神经元存活，突触发生和突触可塑性，并可能在防止与衰老相关的变性中起重要作用。我们将使用多层次方法研究ProbDNF在与衰老相关的记忆障碍基础的海马神经元功能障碍中的作用：行为，药理学，生化和神经解剖学。我们将研究年龄与年轻小鼠海马的ProbDNF处理，并将评估行为任务中BDNF信号传导和记忆缺陷之间的相关性。我们还将在药理上操纵ProbDNF处理，以改善老年动物的记忆力。如果这项研究成功，它将通过确定一组新的分子途径来影响旨在维护老年人的记忆力的未来疗法。公共卫生相关性：与衰老相关的认知下降是60岁及以上的个体的常见状况，估计患病率为20-27％，并且在鉴定痴呆症的临床前阶段很高。记忆任务中的缺陷通常与投射到海马和皮质的海马和胆碱能神经元的功能障碍有关。我们的研究将研究一种分子途径，该途径旨在通过旨在保留老年人的记忆表现的未来疗法。