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

衰老是阿尔茨海默病(AD)的主要风险因素，会导致大脑内细胞和功能的变化，最终导致痴呆症和认知能力下降。延缓或逆转脑老化可延缓阿尔茨海默病的发病，甚至预防阿尔茨海默病的发病，对阿尔茨海默病患者的生活质量和健康负担有很大影响。这项提议检验了一种假设，即年轻的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体可塑性和学习/记忆的下降。TIMP2是一种关键的血源性因子，富含在年轻的血浆中，它能增强海马区激活蛋白1(AP-1)和其他可塑性标记物，同时逆转老年小鼠海马区认知能力的下降。实验将检测年轻的血浆和TIMP2介导的AP-1的增强，AP-1是参与海马体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MMPs。我将研究TIMP2在介导老年海马区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有益效果的必要因素。TIMP2改善海马区功能的机制，包括其作用部位、转录调控的持续时间，以及长期增加TIMP2活性对限制老年小鼠认知能力下降的影响，将被研究。这一结果可能会为旨在恢复TIMP2功能的治疗阿尔茨海默病的治疗提供参考。为了充分表征年轻血浆和血液传播的TIMP2诱导的转录变化，Aim 1将使用下一代测序方法(RNA-SEQ和CHIP-SEQ)，对系统使用年轻血浆、TIMP2或对照组的小鼠老化的海马区组织进行测序。在治疗后，将进行CHIP-SEQ以确定AP-1结合和调控的所有基因。目的2评估TIMP2对青年血浆介导的认知改善和转录改变(在AIM 1中确定)的必要性。接受年轻血浆治疗的小鼠将与接受TIMP2耗尽(或KO)血浆或对照组的小鼠进行比较。目的3采用中和方法研究TIMP2的S作用部位对改善老年海马功能(外周与中枢)的作用。治疗后TIMP2的S转录调控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将被追踪。总之，这些目的是批判性地评估系统性TIMP2在扭转海马区认知衰退方面的作用，以此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.