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: 7533582
• 负责人: JAN Krzysztof BLUSZTAJN
• 金额: $ 39.02万
• 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/7533582
• 关键词: Acetylcholine; Adolescent; Adult; Age; Aging; Animals; Biological Assay; Brain; Brain region; Capital; Cholinergic Agents; Cognitive; Cognitive deficits; Complex; Condition; 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; Week; 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(申请人提供)：衰老与多种认知功能下降有关。特别是，对最近发生的事件形成记忆和学习新的复杂信息的能力往往会减弱。海马体对建立新的记忆至关重要，在动物和人类的研究中有证据表明，高龄会导致海马体结构和神经化学变化，导致其功能受损，导致认知障碍。学习和记忆所必需的海马神经元回路的关键组成部分之一是隔区-海马区通路的神经支配，该通路提供由神经递质乙酰胆碱(ACh)介导的调制输入。这种胆碱能神经支配在大鼠和小鼠出生后的头两周内发育，但其功能在大脑老化时下降。与大多数其他脑区不同，海马区的特点是具有终身的神经发生能力-齿状回神经元前体细胞分裂的结果，其后代可以分化为整合到颗粒细胞层的功能性颗粒神经元。这种神经性活动在幼年动物中很高，但随着年龄的增长而下降。虽然成人神经发生的作用尚不清楚，但有证据表明，它对于正常的海马体功能是必要的，而且老年人大脑中神经发生的受损与认知能力下降有关。海马区的结构和功能受营养因子和分化因子的调节。这些分子调节隔-海马胆碱能通路的建立和维持，以及在正常情况下和对疾病和/或损伤的反应中海马神经细胞的活动。这些营养因子中的一些在海马体出生后早期成熟时表达特别高，在成年时表达较低。我们已经确定了两个这样的幼年因子，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验证这样一种假设，即对衰老的Fischer 344大鼠的大脑给予这些假定的青少年保护因子(BMP9或IGF2)将防止由胆碱能标记物、神经发生和认知能力测定确定的海马区功能的下降或恢复。我们将1)验证BMP9和IGF2作为幼年营养因子在出生后海马发育中的作用，方法是在出生后的关键时期通过脑室内注射中和抗体来降低BMP9和IGF2的水平，以及2)确定脑室注射BMP9或IGF2是否改善了老年大鼠的海马区功能。我们研究的最终目标是将我们的结果与人类记忆中与年龄相关的变化联系起来，并开发有利于人类的青少年营养因子替代策略。衰老与多种认知功能的下降有关。我们已经鉴定出两种蛋白质，骨形态发生蛋白9(BMP9)和胰岛素样生长因子2(IGF2)，它们在幼年脑中含量丰富，但随着脑的成熟而下降。我们以老龄大鼠为模型，提出将这些可能的幼年保护因子(BMP9或IGF2)应用于脑内可以防止与衰老相关的脑功能下降或恢复。我们研究的最终目标是将我们的结果与人类记忆中与年龄相关的变化联系起来，并开发能够使人们受益的青少年生长因子替代策略。