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

R01家长资助摘要，R01AG061382。衰老是老年痴呆症等痴呆症的主要危险因素 疾病。随着美国65岁以上成年人的数量增加，需要新的目标和战略 预计到2040年将达到8000万。尽管传统观点认为可塑性仅限于 老化的大脑，新兴的数据挑战了这一概念，揭示了年轻血液中存在的因素 修复全身老化的组织，同时暗示系统环境和 衰老和阿尔茨海默病相关的大脑变化。通过异种共生分享年轻血液的老龄小鼠 模型或通过血浆移植显示出改善的突触可塑性、树突棘数量和认知能力 表现，这导致我们探索可能与系统性蛋白质因子相关的新的大脑活动 治疗阿尔茨海默氏症。我们最近发表的研究发现，金属蛋白酶组织抑制因子2 (TIMP2)，一种在发育早期的人和年轻的小鼠血浆中比老年血浆中富含的蛋白质， 在调节海马区内的突触可塑性方面扮演着令人惊讶的中心角色(Castellano等人，2017， 自然)。我们发现，TIMP2的治疗显著恢复了海马区的功能 海马区依赖行为任务中的基因表达、长时程增强和记忆表现。 此外，从海马片中去除TIMP2显著减少了LTP及其在血浆消融中的损失 年轻的血浆带来的认知改善。尽管如此，这项工作还是留下了许多基本的 与TIMP2的S在海马区的功能有关的问题，以及它在AD中的作用尚不清楚。近期 工作显示脑脊液血管改变的阿尔茨海默病患者TIMP2水平显著降低 以及血浆中TIMP2靶MMP2水平的变化；我们的初步数据支持TIMP2的扰动 阿尔茨海默病病理模型小鼠的血浆代谢。我们还发现TIMP2的表达 齿状回苔藓细胞内的减少对LTP反应很重要。在这项工作中，我们将探索 中枢神经系统TIMP2直接调节海马区功能的机制及程度 通过改变突触完整性和淀粉样蛋白-β来调节阿尔茨海默病患者的海马区功能 (Aβ)依赖的机制。我们推测TIMP2对正常人的突触功能有调节作用 海马体，在阿尔茨海默病的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机制中的作用 阿尔茨海默病的病理学。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。 海马体的可塑性作用，以及对开发和创造新的AD疗法的启示。

Summary of R01 Parent Grant, R01AG061382. Aging is the major risk factor for dementias such as Alzheimer’s disease. Novel targets and strategies are needed as the number of adults over the age of 65 in the United States is expected to reach 80 million by the year 2040. Though the conventional view holds that plasticity is limited in the aged brain, emerging data have 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 disease-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 us to explore novel brain activities for systemic protein factors that may have relevance for Alzheimer’s disease. Our recently published work uncovered that tissue inhibitor of metalloproteinases 2 (TIMP2), a protein enriched in developmentally early human and young mouse plasma versus aged plasma, plays a surprising central role in regulating synaptic plasticity within the hippocampus (Castellano et al., 2017, Nature). We 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 open many fundamental questions related to TIMP2's function within the hippocampus, and its role in AD remains unexplored. Recent work shows significantly reduced TIMP2 levels in Alzheimer’s disease 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 Alzheimer’s disease 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 Alzheimer’s disease 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 Alzheimer’s disease 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 Alzheimer’s disease pathology. Our aims will interrogate the function of TIMP2, a novel molecule with pro- plasticity roles in the hippocampus, with implications for development and creation of novel AD therapies.