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

衰老是阿尔茨海默病（AD）的主要危险因素，导致大脑内的细胞和功能变化，最终导致痴呆和认知能力下降。减轻或逆转脑老化可延迟阿尔茨海默病发作或甚至防止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。该提案测试了以下假设：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）逆转老年大脑中海马可塑性和学习/记忆的下降。TIMP 2是一种富含于年轻血浆中的关键血液传播因子，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TIMP 2介导的AP-1的增强，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TIMP 2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TIMP 2在多大程度上是年轻血浆所赋予的有益作用的必要因素。将研究TIMP 2改善海马功能的机制，包括其作用位点、其转录控制的持续时间以及长期增加的TIMP 2活性对限制老年小鼠认知能力下降的影响。 这些结果可以为针对恢复TIMP 2功能的治疗提供信息，作为阿尔茨海默病的治疗方法。 为了充分表征由年轻血浆和血源性TIMP 2诱导的转录变化，Aim 1将在来自用年轻血浆、TIMP 2或对照全身治疗的小鼠的老年海马组织中使用下一代测序方法（RNA-seq和ChIP-seq）。将进行ChIP-seq以鉴定处理后AP-1结合和调节的所有基因。目的2评估TIMP 2对于由年轻血浆介导的认知改善和转录变化（在目的1中鉴定）的必要性。将用年幼血浆处理的小鼠与接受TIMP 2耗尽（或KO）血浆或对照的小鼠进行比较。目的3使用中和方法检查TIMP 2的作用位点以改善老年海马功能（外周与中枢）。治疗后TIMP 2转录调节的持续时间以及使用病毒介导方法的长期外周TIMP 2表达的转录和认知后果将被追踪。总之，这些目标批判性地评估了系统性TIMP 2在逆转海马认知下降中的作用，作为限制阿尔茨海默病影响的一种手段。

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.