BMP9 as a juvenile protective factor in cognitive aging

BMP9 作为认知衰老的青少年保护因子

• 批准号: 8629379
• 负责人: JAN Krzysztof BLUSZTAJN
• 金额: $ 33.56万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629379
• 关键词: Acetylcholine; Address; Adolescent; Adult; Age; Aging; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Amyloidosis; Animal Model; Animals; Attention; Autopsy; BMP6 gene; Behavior; Behavioral; Biology; Brain; Cerebral cortex; Cerebrum; Cessation of life; Cognition; Cognitive; Cognitive aging; Collection; Complex; Data; Defect; Dementia; Deposition; Deterioration; Development; Differentiation and Growth; Down-Regulation; Elderly; Enzyme-Linked Immunosorbent Assay; Event; Framingham Heart Study; Functional disorder; Gene Expression Profile; Genes; Goals; Growth Factor; Health; High Prevalence; Hippocampus (Brain); Histopathology; Human; Immunoblotting; Infusion procedures; Injury; Knock-out; Knockout Mice; Learning; Measures; Mediating; Memory; Memory impairment; Mus; Mutation; Neuraxis; Neurons; Neurotransmitters; Patients; Persons; Phenotype; Prevention Measures; Proteins; Sampling; Science; Signal Pathway; Signal Transduction; Slice; Staging; Staining method; Stains; Sterile coverings; System; Techniques; Testing; Therapeutic; Therapeutic Agents; Transgenic Mice; Transgenic Organisms; aged; aging brain; basal forebrain; basal forebrain cholinergic neurons; bone morphogenetic protein 9; cholinergic; cholinergic neuron; cognitive function; effective therapy; efficacy testing; in vivo; indexing; loss of function; memory process; molecular phenotype; morris water maze; mouse model; nerve supply; neuron loss; neuronal circuitry; peptide A; prevent; therapy development; treatment strategy

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.

描述：衰老通常与多种认知功能下降有关。特别是，形成对最近发生的事件的记忆以及吸收新的复杂信息的能力往往会减弱。此外，这些认知缺陷是阿尔茨海默病（AD）等破坏性的、与年龄相关的痴呆症的标志。由于其发病率高且缺乏任何有效的治疗方法，针对这些疾病制定预防措施和治疗策略是生物医学科学的最高优先事项之一。为此目的利用幼体保护因子的概念很有吸引力 - 然而，它提出了两个主要挑战：1）候选因子的识别和表征，以及 2）利用其潜在的治疗益处。拟议的研究重点关注一种引人注目的候选分子——生长和分化因子 2 (GDF2)，通常称为骨形态发生蛋白 9 (BMP9)，及其对认知基础的关键神经元系统的作用。学习、记忆和注意力所必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，它提供由神经递质乙酰胆碱 (ACh) 介导的调节输入。在老年人类和动物、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，推测 BFCN 功能障碍和/或退化会导致高龄和 AD 中出现的记忆缺陷。我们已经获得证据表明 BMP9 是 BFCN 发育过程中的关键分化因子，并且当将 BMP9 注入对这些神经元进行实验性损伤的小鼠脑室内时，可以防止 BFCN 损失。此外，我们的初步数据表明，BMP9 输注可逆转 AD 转基因小鼠模型中 BFCN 标记物的下调，并改善淀粉样变性。这些数据表明BMP9足以支持成人大脑中BFCN的分化和功能；然而我们还不知道 BMP9 在多大程度上对于胆碱能神经元生物学是必需的。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 作为年龄相关认知和 BFCN 功能障碍（重点是 AD）治疗剂的效用。在目标 3 中，我们将探索这样的假设：老年人和 AD 患者的大脑中 BMP 信号可能存在​​异常，使用来自独特病例集合的死后大脑样本，并通过弗雷明汉心脏中心提供彻底的认知和组织病理学评估学习。