Juvenile trophic factors for the prevention and treatment of hippocampal aging

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。海马体对新记忆的建立至关重要，对动物和人类的研究表明，老年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。海马体神经元回路的关键组成部分之一是学习和记忆所必需的，它的神经支配是由间隔-海马体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发育，但其功能随着大脑衰老而下降。与大多数其他脑区不同，海马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，其后代可以分化成整合在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龄动物中很高，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，它对正常的海马功能是必要的，而老年大脑中受损的神经发生与认知能力下降有关。海马的结构和功能受营养因子和分化因子的调控。这些分子在正常情况下以及对疾病和/或损伤的反应中调节中隔海马胆碱能通路和海马神经原性活动的建立和维持。其中一些营养因子的表达在出生后海马的早期成熟中特别高，而在成人中则很低。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的假设，即通过胆碱能标记物、神经发生和认知表现的测定，将这些假定的幼年保护因子（BMP9或IGF2）给予衰老的Fischer 344大鼠的大脑，可以防止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作为幼年营养因子在海马出生后发育中的作用，通过在产后关键时期通过脑室内（icv）给予这些因子的中和抗体来降低它们的水平，2)确定icv给予BMP9或IGF2是否能改善老年大鼠的海马功能。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，并开发出有益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。我们已经确定了两种蛋白质，骨形态发生蛋白9 （BMP9）和胰岛素样生长因子2 (IGF2)，它们在幼年大脑中丰富，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（BMP9或IGF2）给予大脑将防止衰退或导致与衰老相关的脑功能恢复，以老年大鼠为模型。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，并开发出有益于人类的青少年生长因子替代策略。

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.