Juvenile trophic factors for the prevention and treatment of hippocampal aging

幼年营养因子防治海马衰老

• 批准号: 7663150
• 负责人: JAN Krzysztof BLUSZTAJN
• 金额: $ 37.46万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663150
• 关键词: Acetylcholine; Adolescent; Adult; Age; Aging; Animals; Biological Assay; Brain; Brain region; Capital; Cognitive; Cognitive deficits; Complex; Cytoplasmic Granules; Development; Disease; Elderly; Event; Genes; Goals; Growth Factor; Hippocampus (Brain); Human; Impaired cognition; Injection of therapeutic agent; Injury; Insulin-Like Growth Factor II; Learning; Letters; Life; Maintenance; Mediating; Memory; Modeling; Mus; Names; Neurons; Neurotransmitters; Outcome; Pathway interactions; Performance; Prevention; Proteins; Rattus; Recovery; Role; Structure; Testing; adult neurogenesis; aged; aging brain; bone morphogenetic protein 9; cholinergic; cognitive function; dentate gyrus; functional decline; functional disability; granule cell; improved; juvenile animal; nerve supply; neurochemistry; neurogenesis; neuronal circuitry; neutralizing antibody; postnatal; precursor cell; prevent; response; septohippocampal

DESCRIPTION (provided by applicant): Aging is associated with a decline of multiple cognitive functions. In particular, the ability to form memories of recent events and learn new complex information tends to diminish. The hippocampus is critical for the establishment of new memories, and there is evidence from studies in animals and humans that advanced age causes structural and neurochemical changes in the hippocampus that result in its functional impairment, leading to cognitive deficits. One of the key components of the hippocampal neuronal circuitry that is necessary for learning and memory is its innervation by the septo-hippocampal pathway that provides a modulatory input mediated by the neurotransmitter, acetylcholine (ACh). This cholinergic innervations develops during the first two postnatal weeks in rats and mice but its function declines in aging brain. Unlike most other brain regions, the hippocampus is characterized by a life-long capacity for neurogenesis - an outcome of divisions of the dentate gyrus neuronal precursor cells whose progeny can differentiate into functional granule neurons integrated into the granule cell layer. This neurogenic activity is high in the young animal but declines with age. While the role of adult neurogenesis remains to be understood, there is evidence that it is necessary for normal hippocampal function and that impaired neurogenesis in aged brain correlates with cognitive decline. Hippocampal structure and function are regulated by trophic and differentiating factors. These molecules modulate the establishment and maintenance of the septohippocampal cholinergic pathway and hippocampal neurogenic activity under normal conditions and in response to disease and/or injury. The expression of some of these trophic factors is particularly high during early postnatal maturation of the hippocampus and low in the adult. We have identified two such juvenile factors, bone morphogenetic protein 9 (BMP9) and insulin-like growth factor 2 (IGF2). The overall goal of the proposed studies is to test the hypothesis that administration of these putative juvenile protective factors (BMP9 or IGF2) to the brain of aging Fischer 344 rats will prevent the decline or cause a recovery of hippocampal function as determined by assays of cholinergic markers, neurogenesis, and cognitive performance. We will 1) verify that BMP9 and IGF2 function as juvenile trophic factors in postnatal development of the hippocampus by reducing their levels during the critical postnatal periods with intracerebroventricular (icv) administration of neutralizing antibodies against these factors, and 2) determine if the icv administration of BMP9 or IGF2 to aged rats improves hippocampal function. The ultimate goal of our studies is to relate our results to the age-associated changes in memory in humans, and to develop juvenile trophic-factor replacement strategies which could benefit people. Aging is associated with a decline of multiple cognitive functions. We have identified two proteins, bone morphogenetic protein 9 (BMP9) and insulin-like growth factor 2 (IGF2) that are abundant in juvenile brain but decline with brain's maturation and we propose that administration of these putative juvenile protective factors (BMP9 or IGF2) to the brain will prevent the decline or cause a recovery of brain function associated with aging, using old rats as a model. The ultimate goal of our studies is to relate our results to the age-associated changes in memory in humans, and to develop juvenile growth-factor replacement strategies that could benefit people.

描述（由申请人提供）：衰老与多种认知功能的下降有关。特别是，形成最近事件记忆和学习新复杂信息的能力往往会减少。海马对于建立新的记忆至关重要，并且在动物和人类的研究中有证据表明，高龄的人类和神经化学会导致其功能障碍，从而导致认知缺陷。学习和记忆所必需的海马神经元电路的关键组成部分之一是其由隔s-Hampocampal途径的神经支配，该途径提供了由神经递质乙酰胆碱（ACH）介导的调节输入。这种胆碱能神经在大鼠和小鼠的前两个几周内发展，但其功能在衰老的大脑中下降。与大多数其他大脑区域不同，海马的特征是神经发生的终生能力 - 齿状回神经元前体细胞的分裂结果，其后代可以区分成整合到颗粒细胞层中的功能性颗粒神经元。这种神经源性活性在年轻动物中很高，但随着年龄的增长而下降。尽管成人神经发生的作用仍有待理解，但有证据表明，正常海马功能是必要的，并且老年脑中神经发生障碍与认知能力下降相关。海马结构和功能受营养和分化因素的调节。这些分子调节septohampocampal胆碱能途径的建立和维护，以及在正常条件下以及疾病和/或损伤的响应下的海马神经源性活性。这些营养因素中的某些因素的表达在产后早期成熟期间的表达尤其很高，而成年人则低。我们已经确定了两个这样的少年因素，分别是骨形态发生蛋白9（BMP9）和胰岛素样生长因子2（IGF2）。拟议研究的总体目标是检验以下假设：这些假定的少年保护因子（BMP9或IGF2）施用衰老Fischer 344大鼠的大脑将防止通过胆碱能标记，神经发生，和认知能力表现恢复海马功能的下降或导致海马功能的恢复。我们将1）验证BMP9和IGF2在海马后产后发育中充当少年营养因素，通过在关键的产后（ICV）对这些因素进行中和抗体的给药中中和抗体的给药中降低其水平，以及2）是否确定BMP9或IGF2的ICV给药。我们研究的最终目的是将我们的结果与人类记忆的相关记忆变化联系起来，并制定少年营养因素替代策略，从而使人们受益。衰老与多种认知功能的下降有关。我们已经确定了两种蛋白质，分别是骨形态发生蛋白9（BMP9）和类似胰岛素样生长因子2（IGF2），它们在少年大脑中含量丰富，但随着大脑的成熟而下降，我们建议将这些假定的幼年保护因子施用（BMP9或IGF2）（BMP9或IGF2）对大脑的下降或导致与大脑相关的衰老相关的衰老。我们研究的最终目的是将我们的结果与人类记忆的相关记忆变化联系起来，并制定少年生长因素替代策略，从而使人们受益。