Mechanisms of TIMP2-mediated hippocampal revitalization in Alzheimer's disease

项目摘要/摘要：认知功能下降是老年人衰老过程的一个显著特征 老年人口。因为老龄化是许多主要死亡原因的主要风险因素，包括痴呆症 例如阿尔茨海默病(AD)，随着美国人口的增长，需要新的目标和策略 以及更远的地方。尽管传统观点认为老年人大脑的可塑性是有限的，但新兴的数据 对这一概念提出了挑战，揭示了年轻血液中存在的因子可以修复老化的组织 同时暗示系统环境和衰老--以及阿尔茨海默氏症--之间的联系 大脑的相关变化。通过异种共生模型或通过血浆分享幼鼠血液的老龄小鼠 Transfer显示出突触可塑性、树突棘数量和认知能力的改善，这让我 探索可能与阿尔茨海默病相关的系统蛋白因子的新的脑活动。我们最近 已发表的研究发现了金属蛋白酶组织抑制因子2(TIMP2)，这是一种富含 发育早期的人和年轻的小鼠血浆与衰老的血浆相比，起着令人惊讶的中枢作用 在调节海马区突触可塑性中的作用。我发现使用TIMP2的治疗效果显著 恢复海马体功能，通过基因表达、长时程增强和记忆来评估 在海马区依赖行为任务中的表现。此外，从海马片中去除TIMP2 显著降低LTP及其在血浆消融后的损失，这是年轻血浆带来的认知改善。 尽管如此，这项工作仍然留下了许多与TIMP2的S函数相关的基本问题 海马体，它在阿尔茨海默病中的作用仍未被探索。最近的研究表明， 伴有脑脊液血管改变和TIMP2靶向MMP2水平改变的AD患者TIMP2水平降低 在血浆中；我们的初步数据支持阿尔茨海默病小鼠模型血浆中TIMP2代谢的扰动 病理学。我们还发现，TIMP2在齿状回苔藓细胞中的表达减少对 LTP响应。在本工作中，我们将探讨CNS TIMP2直接调节海马区的机制 阿尔茨海默病的功能及TIMP2通过突触完整性改变调节海马区功能的程度 以及淀粉样蛋白β(Aβ)依赖的机制。我们假设TIMP2在脑内调节突触功能。 正常的海马体，在AD病理背景下是恢复性的，主要是通过维持 突触的完整性。我们将在三个主要目标中阐述这一假说：(1)评估小鼠的功能效应 并评价其在苔藓细胞中的作用。 可塑性，(2)评估典型的和假定的TIMP2靶标在海马区的作用，(3)和 研究TIMP2及其相关信号通路在淀粉样蛋白非依赖性和淀粉样依赖性中的作用 AD的病理机制。我们的目标是询问TIMP2的功能，TIMP2是一种具有亲和力的新型分子。 在海马体中的可塑性作用，对AD疗法的开发和创造具有重要意义。

Project Summary/Abstract: Declining cognitive function is a hallmark feature of the aging process in the elderly population. Since aging is the major risk factor for many leading causes of death, including dementias such as Alzheimer's disease (AD), novel targets and strategies are needed as this population grows in the US and beyond. Though the conventional view has held that plasticity is limited in the aged brain, emerging data has challenged this notion, revealing that factors present within young blood are restorative for aged tissues throughout the body while suggesting links between the systemic environment and aging- and Alzheimer's- related changes in the brain. Aged mice sharing young blood via the parabiosis model or through plasma transfer exhibit improved synaptic plasticity, dendritic spine number, and cognitive performance, which led me to explore novel brain activities for systemic protein factors that may have relevance for AD. Our recently published work uncovered tissue inhibitor of metalloproteinases 2 (TIMP2), a protein enriched in developmentally-early human and young mouse plasma versus aged plasma that plays a surprisingly central role in regulating synaptic plasticity within the hippocampus. I showed that treatment with TIMP2 significantly revitalizes hippocampal function, as assessed by gene expression, long-term potentiation, and memory performance in hippocampal-dependent behavioral tasks. Moreover, removing TIMP2 from hippocampal slices dramatically reduced LTP and its loss in plasma ablated cognitive improvements conferred by young plasma. This work has nonetheless left many fundamental questions open related to TIMP2's function within the hippocampus, and its role in Alzheimer's disease remains unexplored. Recent work shows significantly reduced TIMP2 levels in AD patients with vascular changes in CSF and altered levels of TIMP2 target MMP2 in plasma; our preliminary data support a perturbation of TIMP2 metabolism in plasma in mouse models of AD pathology. We also find that TIMP2 expression decreases within dentate gyrus mossy cells important for the LTP response. In this work, we will probe the mechanism by which CNS TIMP2 directly regulates hippocampal function and the extent to which TIMP2 regulates hippocampal function in AD via changes in synaptic integrity as well as amyloid-β (Aβ)-dependent mechanisms. We hypothesize that TIMP2 regulates synaptic function in the normal hippocampus and is restorative in the context of AD pathology, primarily by acting to maintain synaptic integrity. We will address this hypothesis in three major aims: (1) To assess functional effects in mice in which hippocampal TIMP2 has been targeted and to evaluate the contribution of its source in mossy cells to plasticity, (2) to assess the role of canonical and putative TIMP2 targets within the hippocampus, (3) and to investigate the role of TIMP2 and related pathways in amyloid-independent and amyloid-dependent mechanisms of AD pathology. Our aims will interrogate the function of TIMP2, a novel molecule with pro- plasticity roles in the hippocampus, having implications for development and creation of AD therapies.