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（由申请人提供）：衰老与多种认知功能的下降有关。特别是，形成对最近事件的记忆和学习新的复杂信息的能力往往会减弱。海马体对于新记忆的建立至关重要，对动物和人类的研究表明，年老会导致海马体的结构和神经化学变化，导致其功能受损，从而导致认知缺陷。海马神经元回路的关键组成部分之一是学习和记忆所必需的，它受到隔海马通路的神经支配，该通路提供由神经递质乙酰胆碱 (ACh) 介导的调节输入。这种胆碱能神经支配在大鼠和小鼠出生后的前两周内形成，但其功能在衰老的大脑中会下降。与大多数其他大脑区域不同，海马体的特点是具有终生的神经发生能力，这是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中的功能性颗粒神经元。这种神经源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仍有待了解，但有证据表明，它对于正常的海马功能是必要的，并且老年大脑神经发生受损与认知能力下降相关。海马结构和功能受营养和分化因子调节。这些分子在正常条件下以及响应疾病和/或损伤时调节间隔海马胆碱能通路和海马神经源活性的建立和维持。其中一些营养因子的表达在海马出生后早期成熟期间特别高，而在成人中表达较低。我们已经鉴定出两种这样的幼年因子：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检验以下假设：向衰老 Fischer 344 大鼠的大脑施用这些假定的幼年保护因子（BMP9 或 IGF2）将防止海马功能衰退或导致海马功能恢复（根据胆碱能测定确定）标记物、神经发生和认知表现。我们将 1) 通过脑室内 (icv) 注射针对这些因子的中和抗体来降低出生后关键时期 BMP9 和 IGF2 的水平，从而验证 BMP9 和 IGF2 在海马体出生后发育中作为幼年营养因子的功能，以及 2) 确定是否使用 icv 注射BMP9 或 IGF2 给老年大鼠改善海马功能。我们研究的最终目标是将我们的结果与人类年龄相关的记忆变化联系起来，并开发可以造福人类的幼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)，它们在青少年大脑中含量丰富，但随着大脑成熟而减少，我们建议施用这些假定的青少年保护因子（BMP9 或 IGF2）以老年大鼠为模型，对大脑进行治疗将防止与衰老相关的大脑功能衰退或恢复。我们研究的最终目标是将我们的结果与人类年龄相关的记忆变化联系起来，并开发可以造福人类的幼年生长因子替代策略。