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Regulation of hippocampal plasticity and learning and memory by a bloodborne rejuvenation factor

血源性复兴因子对海马可塑性和学习记忆的调节

基本信息

批准号：
9330756
负责人：
Joseph Michael Castellano
金额：
$ 12.77万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9330756
关键词：
Age Age-Months Aging Alzheimer&apos s Disease Amyloid Antibodies Behavioral Blood Brain Brain region CSF2 gene Cause of Death ChIP-seq Cognition Cognitive Complex Dementia Dendritic Spines Disease Dose Environment Gene Expression Gene Targeting Gene Transfer Genes Genetic Transcription Goals Growth Factor Health Heart Diseases Hippocampus (Brain)Human Impaired cognition Infusion procedures Interstitial Collagenase Learning Long-Term Effects MMP3 gene Malignant Neoplasms Matrix Metalloproteinases Mediating Memory Metabolism Methods Mus Muscle Onset of illness Output Parabiosis Pathogenesis Pathway interactions Performance Peripheral Phenotype Plasma Plasma Enhancement Population Protein Microchips Proteins Quality of life Regulation Regulator Genes Rejuvenation Risk Factors Role Shapes Signal Transduction Site Surgical Models Synaptic plasticity TIMP1 gene Testing Therapeutic Effect Thromboplastin Tissue Inhibitor of Metalloproteinases Tissues Transcription Factor AP-1 Transcriptional Regulation Tyrosine 3-Monooxygenase Viral Work activator 1 protein age related aged aging brain aging hippocampus base body system cognitive ability experience experimental study improved insight neurogenesis neuroinflammation neutralizing antibody next generation next generation sequencing novel osmotic minipump overexpression prevent proenkephalin programs transcription factor transcriptome transcriptome sequencing treatment effect

项目摘要

Aging is the major risk factor for Alzheimer’s disease (AD), leading to cellular and functional changes within the brain that culminate in dementia and cognitive decline. Lessening or reversing brain aging may delay Alzheimer’s disease onset or even protect against Alzheimer’s pathogenesis, having a large effect on quality of life and health burden imposed by AD. This proposal tests the hypothesis that young plasma reverses hippocampal decline in plasticity and learning/memory in the aged brain through regulation of transcriptional programs, including gene networks involving Alzheimer’s pathogenesis. TIMP2 is a key blood-borne factor enriched in young plasma that enhances hippocampal Activator-protein 1 (AP-1) and other plasticity markers, while reversing hippocampal cognitive decline in aged mice. Experiments will examine young plasma-mediated and TIMP2-mediated enhancement of AP-1, a transcriptional regulator of genes involved in hippocampal function, including MMPs that are intimately tied to amyloid- metabolism. I will investigate the role of TIMP2 in mediating transcriptional changes in plasticity and Alzheimer’s-related genes in the aged hippocampus and the extent to which TIMP2 is a necessary factor for the beneficial effects conferred by young plasma. The mechanism by which TIMP2 improves hippocampal function, including its site of action, duration of its transcriptional control, and the effect of long-term increased TIMP2 activity on limiting cognitive decline in aged mice will be investigated. The results may inform therapies directed at restoring TIMP2 function as a treatment for Alzheimer’s disease. To fully characterize transcriptional changes induced by both young plasma and blood-borne TIMP2, Aim 1 will use next-generation sequencing methods (RNA-seq and ChIP-seq) in aged hippocampal tissue from mice treated systemically with young plasma, TIMP2, or control. ChIP-seq will be performed to identify all genes bound and regulated by AP-1 following treatment. Aim 2 assesses the necessity of TIMP2 for the cognitive improvements and transcriptional changes (identified in Aim 1) mediated by young plasma. Mice treated with young plasma will be compared to those receiving TIMP2-depleted (or KO) plasma or control. Aim 3 examines TIMP2’s site of action for improvements in aged hippocampal function (peripheral vs central) using a neutralization approach. The duration of TIMP2’s transcriptional regulation following treatment and the transcriptional and cognitive consequences of long-term peripheral TIMP2 expression using a viral-mediated approach will be pursued. Together, these aims critically assess the role of systemic TIMP2 in reversing hippocampal cognitive decline as a means to limit the impact of Alzheimer’s disease.

衰老是阿尔茨海默病 (AD) 的主要危险因素，会导致大脑内的细胞和功能发生变化，最终导致痴呆和认知能力下降。减轻或逆转大脑衰老可能会延缓阿尔茨海默病的发病，甚至可以预防阿尔茨海默病的发病机制，对生活质量和 AD 造成的健康负担有很大影响。该提案测试了这样的假设：年轻血浆通过调节转录程序（包括涉及阿尔茨海默病发病机制的基因网络）来逆转老年大脑中海马可塑性和学习/记忆的下降。 TIMP2 是一种关键的血源性因子，富含于年轻血浆中，可增强海马激活蛋白 1 (AP-1) 和其他可塑性标志物，同时逆转老年小鼠海马认知能力下降。实验将检查年轻血浆介导和 TIMP2 介导的 AP-1 增强作用，AP-1 是参与海马功能的基因的转录调节因子，包括与淀粉样蛋白- 代谢密切相关的 MMP。我将研究 TIMP2 在介导老年海马可塑性和阿尔茨海默病相关基因转录变化中的作用，以及 TIMP2 在多大程度上是年轻血浆赋予的有益作用的必要因素。我们将研究 TIMP2 改善海马功能的机制，包括其作用位点、转录控制的持续时间，以及长期增加 TIMP2 活性对限制老年小鼠认知衰退的影响。这些结果可能为旨在恢复 TIMP2 功能的疗法提供信息，作为阿尔茨海默病的治疗方法。为了充分表征年轻血浆和血源性 TIMP2 诱导的转录变化，Aim 1 将使用新一代测序方法（RNA-seq 和 ChIP-seq）对接受年轻血浆、TIMP2 或对照进行系统治疗的小鼠的老年海马组织进行分析。将进行 ChIP-seq 以鉴定治疗后受 AP-1 结合和调节的所有基因。目标 2 评估 TIMP2 对于年轻血浆介导的认知改善和转录变化（在目标 1 中确定）的必要性。将用年轻血浆处理的小鼠与接受TIMP2耗尽（或KO）血浆或对照的小鼠进行比较。目标 3 使用中和方法检查 TIMP2 的作用位点，以改善老年海马功能（外周与中枢）。将探究治疗后 TIMP2 转录调节的持续时间，以及使用病毒介导的方法长期外周 TIMP2 表达的转录和认知后果。总之，这些目标严格评估了全身性 TIMP2 在逆转海马认知衰退中的作用，作为限制阿尔茨海默病影响的一种手段。