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

项目概要/摘要：认知功能下降是老年人衰老过程的一个标志性特征， 老年人口。由于衰老是许多主要死亡原因的主要风险因素，包括痴呆症 如阿尔茨海默氏病（AD），随着这一人群在美国的增长，需要新的靶点和策略 以及更远的地方尽管传统观点认为老年人的大脑可塑性有限，但新的数据显示， 挑战了这一观点，揭示了年轻血液中存在的因子对衰老组织具有恢复作用 同时表明系统环境与衰老和阿尔茨海默氏症之间的联系， 大脑中的相关变化。通过联体共生模型或通过血浆共享年轻血液的老年小鼠 转移表现出改善的突触可塑性，树突棘数量和认知能力，这使我 探索可能与AD相关的系统性蛋白质因子的新脑活动。我们最近 已发表的工作揭示了金属蛋白酶组织抑制剂2（TIMP 2），一种富含金属蛋白酶的蛋白质。 发育早期的人类和年轻小鼠血浆与老年血浆相比， 调节海马内突触可塑性的作用。我发现用TIMP 2治疗， 通过基因表达、长时程增强和记忆评估， 在依赖于露营的行为任务中的表现。此外，从海马切片中去除TIMP 2 显著降低LTP及其在血浆中的损失消融了由年轻血浆赋予的认知改善。 尽管如此，这项工作仍然留下了许多与TIMP 2在细胞内的功能有关的基本问题。 海马体，其在阿尔茨海默病中的作用仍有待研究。最近的研究显示， 在伴有CSF血管变化和TIMP 2靶点MMP 2水平改变的AD患者中降低TIMP 2水平 我们的初步数据支持在AD小鼠模型中血浆中TIMP 2代谢的扰动 病理我们还发现，TIMP 2在齿状回苔藓细胞中的表达减少，这对海马神经元的凋亡非常重要。 LTP反应。在这项工作中，我们将探讨CNS TIMP 2直接调节海马神经元的机制， 功能和TIMP 2通过突触完整性的变化调节AD中海马功能的程度 以及淀粉样蛋白-β（Aβ）依赖性机制。我们假设TIMP 2调节突触功能， 在AD病理学的背景下是恢复性的，主要通过作用于维持 突触完整性。我们将从三个主要目标来阐述这一假设：（1）评估小鼠的功能效应 其中海马TIMP 2已被靶向，并评估其在苔藓细胞中的来源对 可塑性，（2）评估海马内典型和假定的TIMP 2靶点的作用，（3） 研究TIMP 2和相关通路在淀粉样蛋白非依赖性和淀粉样蛋白依赖性 AD病理机制。我们的目标是询问TIMP 2的功能，TIMP 2是一种具有促凋亡作用的新型分子， 可塑性的作用，在海马体中，有意义的发展和创造的AD疗法。

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.