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：
8277213
负责人：
Mona Buhusi
金额：
$ 1.21万
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 2012-08-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8277213
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.

描述（由申请人提供）：与衰老相关的认知能力下降是 60 岁及以上人群中的常见病症，患病率估计为 20-27%，对于识别痴呆症的临床前阶段非常有用。记忆任务的缺陷通常与海马体和投射到海马体和皮质的胆碱能神经元的功能障碍有关。虽然目前针对神经退行性疾病和认知缺陷的疗法主要集中在氧化应激的神经保护和支持乙酰胆碱神经传递上，但该项目提出了前神经营养蛋白的蛋白水解加工的范式的改变。神经营养蛋白及其前体之间的平衡调节发育中和成年大脑中至关重要的过程，包括神经元存活、突触发生和突触可塑性，并且可能在预防与衰老相关的退化中发挥重要作用。我们将使用行为、药理学、生化和神经解剖学等多层次方法研究 proBDNF 在与衰老相关的记忆障碍相关的海马神经元功能障碍中的作用。我们将研究老年小鼠与年轻小鼠海马体中的 proBDNF 处理，并且我们将评估行为任务中 BDNF 信号传导与记忆缺陷之间的相关性。我们还将通过药理学手段操纵 proBDNF 加工，以提高老年动物的记忆性能。如果这项研究成功，它将通过确定一组新的治疗目标分子途径来影响未来旨在保持老年人记忆能力的治疗方法。