Study ApoE4's Effects on Hippocampal Network Activity in Alzheimer's Disease

项目总结 阿尔茨海默病(AD)的复杂性和多因素特性对机械学提出了独特的挑战 研究和开发治疗方法。在动物研究中，靶向AD相关通路的努力显示出了希望。 但在人体试验中却失败了。因此，仍然迫切需要确定新的机制和 治疗或预防AD的治疗靶点。 AD病理最早的部位之一是海马体，这是一种对学习和学习至关重要的大脑结构 记忆过程在AD早期步履蹒跚。几十年的研究已经对遗传学和 这种疾病的细胞病理，但尚不清楚这些病理如何破坏海马体记忆 流程。阿尔茨海默病的主要遗传风险因素是载脂蛋白E4，它降低了阿尔茨海默病的发病年龄 以基因剂量依赖的方式。在大多数临床研究中，载脂蛋白E4携带者占所有AD的60%-75% 2例，突出载脂蛋白E4在AD发病机制中的重要性。尽管许多假说已经被 目前，apoE4的病理生理作用的细胞和网络机制仍然是 不清楚。 这一建议建立在我们最近对老鼠模型的研究中的新发现之上。第一，apoE4的表达 基因敲除(KI)小鼠脑门GABA能中间神经元的增龄损伤 海马体，它与学习和记忆缺陷的严重程度相关。第二、删除apoE4 GABA能中间神经元特异性基因预防肝门区中间神经元丢失和学习记忆障碍 在loxP-FKI(apoE4-FKI)小鼠中。第三，活体局部场电位(LFP)记录 海马环路显示，与老年apoE3-ki小鼠相比，老年apoE4-ki小鼠的尖锐波较少 涟漪(SWR)事件-对记忆重播和巩固至关重要的海马体网络事件-并具有 极大地减少了短波辐射期间的缓慢伽马活动，以协调短波辐射。第四，消除 GABA能中间神经元ApoE4挽救SWR相关的慢伽马活动，但不能挽救SWR的丰度 ApoE4-FKI小鼠，提示SWRS期间中间神经元激活的慢伽马活动的中断是一种 载脂蛋白E4介导的学习和记忆障碍的关键机制。本提案旨在(1)确定 抑制性中间神经元亚型在apoE4破坏海马区网络活动中的相对作用 基础记忆重播和(2)确定apoE4是否破坏了海马区的网络活动 底层内存重放取决于Aβ和/或tau。拟议中的研究结果将揭示 探讨晚发性AD的发病机制，为开发治疗AD的药物提供新的靶点 预防AD。

PROJECT SUMMARY The complexity and multifactorial nature of Alzheimer's disease (AD) poses unique challenges for mechanistic studies and developing therapies. Efforts to target AD-related pathways have shown promise in animal studies, only to fail during human trials. Thus, there remains a pressing need to identify novel mechanisms and therapeutic targets for treating or preventing AD. One of the earliest sites of AD pathology is the hippocampus, a brain structure critical for the learning and memory processes that falter early in AD. Decades of research have yielded insight into the genetics and cellular pathologies of the disease, but it is unclear how these pathologies disrupt hippocampal memory processes. The main genetic risk factor for AD is apolipoprotein (apo) E4, which lowers the age of onset of AD in a gene dose–dependent manner. In most clinical studies, apoE4 carriers account for 60–75% of all AD cases, highlighting the importance of apoE4 in AD pathogenesis. Although many hypotheses have been proposed, the cellular and network mechanisms underlying the pathophysiological actions of apoE4 are still unclear. This proposal builds on novel findings from our recent studies of mouse models. First, expression of apoE4 in knock-in (KI) mice causes age-dependent impairment of GABAergic interneurons in the hilus of the hippocampus, which correlates with the severity of learning and memory deficits. Second, deleting the apoE4 gene specifically in GABAergic interneurons prevents hilar interneuron loss and learning and memory deficits in LoxP-floxed apoE4-KI (apoE4-fKI) mice. Third, in vivo local field potential (LFP) recordings throughout the hippocampal circuit shows that compared to aged apoE3-KI mice, aged apoE4-KI mice have fewer sharp wave ripple (SWR) events—hippocampal network events critical for memory replay and consolidation—and have significantly reduced slow gamma activity during SWRs, which coordinates SWRs. Fourth, elimination of apoE4 in GABAergic interneurons rescues SWR-associated slow gamma activity but not SWR abundance in apoE4-fKI mice, suggesting that the disruption of interneuron-enabled slow gamma activity during SWRs is a critical mechanism of apoE4-mediated learning and memory impairments. This proposal aims (1) to determine the relative contribution of inhibitory interneuron subtypes to apoE4 disruption of hippocampal network activity underlying memory replay and (2) to determine whether apoE4 disruption of hippocampal network activity underlying memory replay depends on Aβ, tau, or both. The outcomes of the proposed studies will shed light on the pathogenesis of late-onset AD and could provide new targets for developing drugs treating or preventing AD.