Role of BMP Signaling in the Aging Brain

BMP 信号传导在大脑衰老中的作用

• 批准号: 10180811
• 负责人: JOHN A KESSLER
• 金额: $ 30.7万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10180811
• 关键词: Ablation; Affect; Affective; Age; Age-Months; Age-associated memory impairment; Aging; Anatomy; Anxiety; Anxiety Disorders; Autopsy; BMPR2 gene; Behavior; Behavioral; Biochemical; Brain; Cognition; Cognitive; Development; Exercise; Genetic; Goals; Growth; Hippocampus (Brain); Human; Impairment; Intervention; Intraventricular Infusion; Knowledge; Label; Lead; Ligands; Measures; Mediating; Mental Depression; Molecular; Mus; Nervous System Physiology; Nervous system structure; Organ; Performance; Peripheral; Physiological; Process; Proliferation Marker; Property; RNA Interference Therapy; Receptor Signaling; Risk; Rodent; Role; Signal Transduction; Spherical Nucleic Acids; Structure; System; Testing; Therapeutic; Therapeutic Intervention; Time; Transgenic Organisms; adult neurogenesis; age related; aged; aging brain; aging hippocampus; bone morphogenetic protein 4; bone morphogenetic protein receptors; cell type; cognitive function; cognitive performance; cognitive task; dentate gyrus; druggable target; functional decline; improved; inhibitor/antagonist; nanoparticle; nerve stem cell; neuroblast; neurogenesis; new technology; nonhuman primate; overexpression; prevent; receptor; receptor expression; relating to nervous system; stem; stem cells; targeted treatment; therapeutic target

Project Summary Aging often leads to a functional decline across multiple cognitive domains, and there is a signficantly increased risk of depression and anxiety disorders in the aged. However, the physiologic and anatomic changes underlying these impairments are not fully understood. A number of changes in hippocampal structure and connectivity are associated with aging including a decline in neurogenesis in the subgranular zone of the dentate gyrus (DG) and decreased performance on hippocampus-dependent tasks. Levels of bone morphogenetic protein 4 (BMP4) in the mouse DG increase more than 10-fold between 8 and 52 weeks of age. A similar aging- related increase in BMP4 expression is found in the human DG. Conversely, levels of the BMP inhibitor, noggin, in the mouse DG decrease by about 70% during this time. This results in an extraordinary 30-fold aging-related increase in BMP signaling in the DG measured by levels of phosph-SMAD1/5/8. Reducing BMP signaling in aged mice by either intraventricular infusion or transgenic overexpression of noggin reverses aging-related changes in both neurogenesis and cognition, and it reduces depression-like behavior. Conversely, transgenic overexpression or intraventricular infusion of BMP4 in aged mice prevents the beneficial effects of exercise on neurogenesis and on cognitive and affective behavior. These findings lead to the hypothesis that changes in BMP signaling underlie the decreases in neurogenesis and in hippocampus- dependent behavior associated with aging. To test this hypothesis, we will first investigate the cellular and behavioral effects of inducible cre-mediated ablation of BMPRII in neural stem cells in the DG of aged mice. We then will examine the potential causal relationship between changes in neurogenesis and behavior. To begin to develop a potential therapeutic approach, we will use a new technology, spherical nucleic acid nanoparticle conjugates (SNAs), as an RNAi-based therapeutic approach to enable us to specifically target BMPR signaling in the brain to enhance adult neurogenesis. Finally, we will define changes in expression and cellular origin of BMP ligands, receptors, and inhibitors in the hippocampus of aging humans and examine correlations between BMP levels, neurogenesis, and age-associated cognitive decline in humans. The goal of the studies is to identify specific molecular loci where therapeutic intervention in the aged nervous system may lead to a return to normal neurological function.

项目总结

项目成果

Why Some Mice Are Smarter than Others: The Impact of Bone Morphogenetic Protein Signaling on Cognition.

为什么有些小鼠比其他小鼠更聪明：骨形态发生蛋白信号对认知的影响。

• DOI: 10.1523/eneuro.0213-22.2022
• 发表时间: 2023
• 期刊: eNeuro
• 影响因子: 3.4
• 作者: Bonds,JacquelineA;Tunc-Ozcan,Elif;Dunlop,SaraR;Rawat,Radhika;Peng,Chian-Yu;Kessler,JohnA
• 通讯作者: Kessler,JohnA