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

R 01父母补助金汇总，R 01 AG 061382。衰老是老年痴呆症等痴呆症的主要危险因素 疾病需要新的目标和策略，因为美国65岁以上的成年人数量 预计到2040年将达到8000万。虽然传统观点认为可塑性是有限的， 随着大脑老化，新的数据挑战了这一概念，揭示了年轻血液中存在的因素 恢复整个身体的老化组织，同时表明系统环境和 衰老和阿尔茨海默病相关的大脑变化。老龄小鼠通过联体共生共享年轻血液 模型或通过血浆转移表现出改善的突触可塑性、树突棘数量和认知功能。 性能，这使我们探索新的大脑活动的系统蛋白质因素，可能有相关性 治疗阿尔茨海默病我们最近发表的工作揭示了金属蛋白酶组织抑制剂2 TIMP 2，一种在发育早期人和年轻小鼠血浆中相对于老年血浆富集的蛋白质， 在调节海马内的突触可塑性中起着令人惊讶的中心作用（Castellano等，2017, Nature）。我们发现用TIMP 2治疗显著地恢复了海马功能， 基因表达，长时程增强，和记忆表现在海马依赖的行为任务。 此外，从海马切片中去除TIMP 2显著降低了LTP及其在血浆消融中的损失。 年轻血浆带来的认知改善这项工作仍然留下了许多基本的开放 与TIMP 2在海马体内的功能相关的问题及其在AD中的作用尚未得到探讨。最近 研究显示，在具有CSF中血管变化的阿尔茨海默病患者中， 和血浆中TIMP 2靶向MMP 2水平的改变;我们的初步数据支持TIMP 2的扰动 在阿尔茨海默氏病病理学的小鼠模型中，血浆中的代谢。我们还发现TIMP 2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，我们将探讨 CNS TIMP 2直接调节海马功能的机制以及TIMP 2 通过突触完整性和β淀粉样蛋白的变化调节阿尔茨海默病中的海马功能 （Aβ）依赖性机制。我们假设TIMP 2调节正常人的突触功能 在阿尔茨海默病病理学的背景下是恢复性的，主要是通过作用于维持 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机制中的作用 阿尔茨海默病的病理学。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，与发展和创造新的AD疗法的影响。

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.