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: 9087080
• 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/9087080
• 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; Cognitive deficits; 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; 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; brain dysfunction; 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; spatial memory; 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：衰老经常与多种认知功能的下降有关。特别是，形成最近事件的记忆并吸收新的和复杂信息的能力往往会减少。此外，这些认知缺陷是毁灭性，与年龄相关的痴呆症的标志，例如阿尔茨海默氏病（AD）。由于其高患病率和缺乏任何有效的疗法，因此针对这些疾病的预防措施和治疗策略的发展构成了生物医学科学的最高优先事项之一。为此目的，利用少年保护因素的概念具有吸引力 - 但是，它提出了两个核心挑战：1）候选因素的识别和表征，以及2）其利用其对治疗益处的利用。拟议的研究集中于引人入胜的候选分子 - 生长和分化因子2（GDF2），更常见地称为骨形态发生蛋白9（BMP9）及其对基于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元电路的关键组成部分之一是基础前脑胆碱能神经元（BFCN）对海马和脑皮质的神经支配，这些神经元（BFCN）提供了由Neurotransmitter，乙酰胆碱（ACH）介导的调节输入。在AD患者和AD的动物模型中，BFCN功能的下降和胆碱能标记的表达降低是显而易见的。因此，已经假定BFCN的功能障碍和/或退化有助于高龄和AD中看到的记忆缺陷。我们已经获得了证据表明，BMP9是开发过程中BFCN的关键因素，并且当在对这些神经元的实验损伤的小鼠中注入脑室时，可以防止BFCN损失。此外，我们的初步数据表明，BMP9输注逆转AD的转基因小鼠模型中看到的BFCN标记的下调，并改善了淀粉样变性。这些数据表明，BMP9足以支持成人大脑中的BFCN分化和功能。但是，我们尚不知道胆碱能神经元生物学的BMP9在多大程度上。在AIM 1中，这个中心问题将通过对BMP9敲除小鼠的功能丧失研究来解决。在AIM 2中，我们将使用转基因小鼠模型测试BMP9作为年龄相关的认知和BFCN功能障碍的治疗剂的实用性，重点是AD。在AIM 3中，我们将探讨以下假设：使用弗雷明汉心脏研究获得的彻底认知和组织病理学评估的独特病例收集的尸体后脑样本，BMP信号传导在衰老的人和AD患者的大脑中可能是异常的。