BMP9 as a juvenile protective factor in cognitive aging

描述：衰老通常与多种认知功能的下降有关。特别是，对最近发生的事件形成记忆和吸收新的复杂信息的能力往往会减弱。此外，这些认知缺陷是毁灭性的、与年龄相关的痴呆的特征，如阿尔茨海默病(AD)。由于它们的高患病率和缺乏任何有效的治疗方法，为这些疾病制定预防措施和治疗战略是生物医学科学的最高优先事项之一。为此目的利用青少年保护因素的概念很有吸引力--然而，它提出了两个核心挑战：1)确定和表征候选因素，2)利用其治疗效益的潜力。拟议的研究集中在一个引人注目的候选分子-生长和分化因子2(GDF2)，通常被称为骨形态发生蛋白9(BMP9)，以及它在构成认知基础的关键神经系统中的作用。学习、记忆和注意所必需的神经元回路的关键组成部分之一是基底前脑胆碱能神经元(BFCN)对海马和大脑皮层的神经支配，BFCN由神经递质乙酰胆碱(ACh)介导的调制输入。在老年人和动物、AD患者和AD动物模型中，BFCN功能下降和胆碱能标志物表达减少是明显的。因此，人们推测BFCN的功能障碍和/或退行性改变与老年和AD患者的记忆缺陷有关。我们已经获得证据表明，BMP9是BFCN在发育过程中的关键区分因子，当在实验性损伤这些神经元的小鼠脑室内注入BMP9时，可以防止BFCN丢失。此外，我们的初步数据显示，BMP9输注逆转了转基因AD小鼠模型中BFCN标志物的下调，并改善了淀粉样变性。这些数据表明，BMP9足以支持BFCN在成人脑中的分化和功能；然而，我们还不知道BMP9在多大程度上是胆碱能神经元生物学所必需的。在目标1中，这个中心问题将通过对BMP9基因敲除小鼠的功能丧失研究来解决。在目标2中，我们将使用转基因小鼠模型来测试BMP9作为治疗与年龄相关的认知和BFCN功能障碍的药物的效用，重点是AD。在目标3中，我们将探索BMP信号可能在老龄化人类和AD患者的大脑中异常的假设，使用来自一组独特的病例的死后大脑样本，这些病例具有彻底的认知和组织病理学评估，可通过Framingham心脏研究获得。

DESCRIPTION: Aging is frequently associated with a decline in multiple cognitive functions. In particular, the ability to form memories of recent events and assimilate new and complex information tends to diminish. Moreover, these cognitive defects are hallmarks of devastating, age-associated dementias such as Alzheimer's disease (AD). Due to their high prevalence and the lack of any effective therapies, the development of prevention measures and treatment strategies for these conditions constitutes one of the highest priorities of the biomedical sciences. The concept of utilizing juvenile protective factors for this purpose is an attractive on - however, it presents two central challenges: 1) the identification and characterization of a candidate factor, and 2) the utilization of its potential for therapeutic benefit. The proposed studies focus on a compelling candidate molecule - growth and differentiation factor 2 (GDF2), more commonly referred to as bone morphogenetic protein 9 (BMP9), and its actions on critical neuronal systems that underlie cognition. One of the key components of the neuronal circuitry necessary for learning, memory and attention is the innervation of the hippocampus and cerebral cortex by basal forebrain cholinergic neurons (BFCN), which provide modulatory input mediated by the neurotransmitter, acetylcholine (ACh). A decline in BFCN function and diminished cholinergic marker expression is apparent in aged humans and animal, in AD patients, and in animal models of AD. Thus, it has been postulated that dysfunction and/or degeneration of BFCN contributes to the memory deficits seen in advanced age and in AD. We have obtained evidence that BMP9 is a key differentiating factor for BFCN during development and, when infused intracerebroventricularly in mice with experimental injury to these neurons, prevents BFCN loss. Moreover, our preliminary data show that BMP9 infusion reverses the downregulation of BFCN markers seen in a transgenic mouse model of AD and ameliorates amyloidosis. These data indicate that BMP9 is sufficient to support BFCN differentiation and function in the adult brain; however we do not yet know to what extent BMP9 is necessary for cholinergic neuron biology. In aim 1 this central question will be addressed by loss-of-function studies on Bmp9 knockout mice. In aim 2 we will test the utility of BMP9 as a therapeutic agent for age-associated cognitive and BFCN dysfunction, with the focus on AD, using transgenic mouse models. In aim 3, we will explore the hypothesis that BMP signaling may be abnormal in the brains of aging humans and AD patients, using post-mortem brain samples from a unique collection of cases with a thorough cognitive and histopathological assessment, available through the Framingham Heart Study.