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

项目摘要 阿尔茨海默病（AD）的复杂性和多因素性对机制研究提出了独特的挑战。 研究和开发疗法。针对AD相关通路的努力在动物研究中显示出希望， 却在人体试验中失败了因此，仍然迫切需要确定新的机制， 用于治疗或预防AD的治疗靶点。 AD病理学的最早部位之一是海马体，海马体是对学习和认知至关重要的脑结构。 记忆过程在AD早期就开始衰退几十年的研究已经深入了解了遗传学， 这种疾病的细胞病理学，但目前还不清楚这些病理学如何破坏海马记忆 流程. AD的主要遗传危险因素是载脂蛋白（apo）E4，其降低AD的发病年龄 以基因剂量依赖的方式。在大多数临床研究中，apoE 4携带者占所有AD的60- 75 例，突出了apoE 4在AD发病机制中的重要性。虽然有很多假设 尽管已经提出，apoE 4的病理生理学作用的细胞和网络机制仍然是未知的。 不清楚 这一提议建立在我们最近对小鼠模型研究的新发现基础上。第一，apoE 4的表达 在基因敲入（KI）小鼠中，引起门区GABA能中间神经元的年龄依赖性损伤， 海马，这与学习和记忆缺陷的严重程度相关。第二，删除apoE 4 GABA能中间神经元特异性基因可防止门部中间神经元丢失和学习记忆缺陷 在LoxP-floxed apoE 4-KI（apoE 4-fKI）小鼠中。第三，在体内局部场电位（LFP）记录整个 海马回路显示，与老年apoE 3-KI小鼠相比，老年apoE 4-KI小鼠具有较少的尖波 涟漪（SWR）事件-海马网络事件对记忆重放和巩固至关重要-并且具有 显著降低了SWR期间的慢伽马放射性，其协调SWR。第四，消除 GABA能中间神经元中的apoE 4挽救了SWR相关的慢γ活性，但没有挽救 apoE 4-fKI小鼠，这表明在SWR过程中， apoE 4介导的学习和记忆障碍的关键机制。本建议旨在（1）确定 抑制性中间神经元亚型对apoE 4破坏海马网络活动相对贡献 潜在的记忆重放和（2）确定apoE 4是否破坏海马网络活动 潜在的记忆重放取决于Aβ、tau或两者。拟议研究的结果将揭示 研究晚发性AD的发病机制，为开发治疗或 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.