BMP9 as a juvenile protective factor in cognitive aging

衰老通常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吸收新的和复杂信息的能力往往会减弱。此外，这些认知缺陷是破坏性的、与年龄相关的痴呆症（如阿尔茨海默病（AD））的标志。由于这些疾病的高发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子的概念是一个有吸引力的，然而，它提出了两个核心挑战：1)候选因子的识别和表征，以及2)利用其潜在的治疗益处。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)，更通常被称为骨形态发生蛋白9 (BMP9)，及其对认知基础的关键神经系统的作用。学习、记忆和注意所需的神经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，这些神经元提供由神经递质乙酰胆碱（ACh）介导的调节输入。在老年人和动物、阿尔茨海默病患者和阿尔茨海默病动物模型中，BFCN功能下降和胆碱能标志物表达减少是明显的。因此，人们假设BFCN的功能障碍和/或退化导致了老年和AD患者的记忆缺陷。我们已经获得证据表明BMP9在发育过程中是BFCN的关键分化因子，当在这些神经元实验性损伤的小鼠脑室内注入BMP9时，可以防止BFCN的丢失。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标记物的下调，并改善了淀粉样变性。这些数据表明，BMP9足以支持BFCN在成人大脑中的分化和功能；然而，我们还不知道BMP9在多大程度上对胆碱能神经元生物学是必要的。在目标1中，这个核心问题将通过Bmp9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测试BMP9作为与年龄相关的认知和BFCN功能障碍治疗剂的效用，重点是AD。在目标3中，我们将探索BMP信号可能在衰老人类和AD患者的大脑中异常的假设，使用来自弗雷明汉心脏研究中提供的具有全面认知和组织病理学评估的独特病例的死后脑样本。

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.