Memory and ProBDNF Processing in the Aged Mouse Hippocampus

老年小鼠海马体的记忆和 ProBDNF 处理

• 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
• 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

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）：衰老相关的认知能力下降是60岁及以上人群的常见疾病，患病率估计为20- 27%，并且在痴呆症临床前阶段的识别中具有很高的用途。记忆任务的缺陷通常与海马以及投射到海马和皮质的胆碱能神经元的功能障碍有关。 虽然目前的神经变性和认知缺陷的治疗集中在神经保护氧化应激和支持乙酰胆碱神经传递，该项目提出了一个范式的变化，对蛋白水解加工的神经营养素原。神经营养因子及其前体之间的平衡调节发育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，并可能在预防衰老相关的退化中发挥重要作用。 我们将使用多层次的方法：行为，药理学，生物化学和神经解剖学，研究脑源性神经营养因子原在海马神经元功能障碍中的作用，这些功能障碍是衰老相关的记忆障碍的基础。我们将调查proBDNF处理在老年与年轻小鼠海马，我们将评估BDNF信号和记忆缺陷之间的相关性在行为任务。我们还将对proBDNF的加工过程进行人工操纵，以提高老年动物的记忆力。 如果这项研究成功，它将通过确定一组新的分子通路来影响未来旨在保护老年人记忆能力的治疗方法。 公共卫生关系：与衰老相关的认知能力下降是60岁及以上人群中常见的疾病，患病率估计为20- 27%，并且对于痴呆症的临床前阶段的识别具有很高的用途。记忆任务的缺陷通常与海马以及投射到海马和皮质的胆碱能神经元的功能障碍有关。我们的研究将调查一种分子途径，该途径将被未来旨在保持老年人记忆能力的疗法所靶向。