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标志性特征 老年人口。由于衰老是许多主要死亡原因（包括痴呆症）的主要风险因素 例如阿尔茨海默病 (AD)，随着美国这一人群的增长，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，但新出现的数据 挑战了这一观点，揭示了年轻血液中存在的因子可以恢复衰老的组织 整个身体，同时表明全身环境与衰老和阿尔茨海默病之间的联系 大脑的相关变化。老年小鼠通过联体共生模型或血浆共享年轻血液 转移表现出突触可塑性、树突棘数量和认知能力的改善，这让我 探索可能与 AD 相关的全身蛋白因子的新大脑活动。我们最近 已发表的工作揭示了金属蛋白酶组织抑制剂 2 (TIMP2)，这是一种富含 发育早期的人类和年轻小鼠血浆与老年血浆的比较，其中发挥着令人惊讶的核心作用 调节海马内突触可塑性的作用。我证明 TIMP2 治疗显着 通过基因表达、长时程增强和记忆力评估，恢复海马功能 海马依赖性行为任务的表现。此外，从海马切片中去除 TIMP2 显着降低 LTP 及其在血浆中的损失，消除了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 在 TIMP2 中的功能相关的基本问题。 海马体及其在阿尔茨海默病中的作用仍未被探索。最近的工作显着地表明 AD 患者的 TIMP2 水平降低，脑脊液血管发生变化，并且 TIMP2 靶标 MMP2 水平发生改变 在血浆中；我们的初步数据支持 AD 小鼠模型血浆中 TIMP2 代谢的扰动 病理学。我们还发现齿状回苔藓细胞内 TIMP2 表达降低，这对于 LTP 响应。本工作将探讨CNS TIMP2直接调控海马的机制 功能以及 TIMP2 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 TIMP2 调节突触功能 正常海马体，在 AD 病理学背景下具有恢复性，主要通过维持 突触完整性。我们将通过三个主要目标来解决这一假设：（1）评估小鼠的功能影响 其中海马 TIMP2 已成为目标，并评估其在苔藓细胞中的来源对 可塑性，(2) 评估海马体内典型和假定的 TIMP2 靶标的作用，(3) 并 研究 TIMP2 和相关通路在淀粉样蛋白非依赖性和淀粉样蛋白依赖性中的作用 AD 病理机制。我们的目标是探究 TIMP2 的功能，TIMP2 是一种具有亲和性的新型分子。 海马体中的可塑性作用，对 AD 疗法的开发和创造具有影响。

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.