Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD), increasing risk and decreasing age of disease onset. Many studies have demonstrated the detrimental effects of apoE4 in varying cellular contexts. However, the underlying mechanisms explaining how apoE4 leads to cognitive decline are not fully understood. Recently, the combination of human induced pluripotent stem cell (hiPSC) modeling of neurological diseases in vitro and electrophysiological studies in vivo have begun to unravel the intersection between apoE4, neuronal subtype dysfunction or loss, subsequent network deficits, and eventual cognitive decline. In this review, we provide an overview of the literature describing apoE4's detrimental effects in the central nervous system (CNS), specifically focusing on its contribution to neuronal subtype dysfunction or loss. We focus on γ-aminobutyric acid (GABA)-expressing interneurons in the hippocampus, which are selectively vulnerable to apoE4-mediated neurotoxicity. Additionally, we discuss the importance of the GABAergic inhibitory network to proper cognitive function and how dysfunction of this network manifests in AD. Finally, we examine how apoE4-mediated GABAergic interneuron loss can lead to inhibitory network deficits and how this deficit results in cognitive decline. We propose the following working model: Aging and/or stress induces neuronal expression of apoE. GABAergic interneurons are selectively vulnerable to intracellularly produced apoE4, through a tau dependent mechanism, which leads to their dysfunction and eventual death. In turn, GABAergic interneuron loss causes hyperexcitability and dysregulation of neural networks in the hippocampus and cortex. This dysfunction results in learning, memory, and other cognitive deficits that are the central features of AD.

中文翻译：

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载脂蛋白 E4、抑制网络功能障碍和阿尔茨海默病。


载脂蛋白 (apo) E4 是阿尔茨海默病 (AD) 的主要遗传风险因素，会增加患病风险并降低发病年龄。许多研究已经证明 apoE4 在不同细胞环境中的有害影响。然而，解释 apoE4 如何导致认知能力下降的根本机制尚不完全清楚。最近，人类诱导多能干细胞 (hiPSC) 神经疾病体外模型和体内电生理学研究相结合，已经开始揭示 apoE4、神经元亚型功能障碍或缺失、随后的网络缺陷和最终认知能力下降之间的交叉点。在这篇综述中，我们概述了描述 apoE4 对中枢神经系统 (CNS) 有害影响的文献，特别关注其对神经元亚型功能障碍或丧失的影响。我们关注海马中表达 γ-氨基丁酸 (GABA) 的中间神经元，这些神经元选择性地容易受到 apoE4 介导的神经毒性的影响。此外，我们还讨论了 GABA 能抑制网络对正常认知功能的重要性以及该网络的功能障碍在 AD 中的表现。最后，我们研究了 apoE4 介导的 GABA 能中间神经元丢失如何导致抑制性网络缺陷以及这种缺陷如何导致认知能力下降。我们提出以下工作模型：衰老和/或压力诱导 apoE 的神经元表达。 GABA 能中间神经元通过 tau 依赖性机制选择性地受到细胞内产生的 apoE4 的影响，从而导致其功能障碍并最终死亡。反过来，GABA能中间神经元损失会导致海马和皮层神经网络过度兴奋和失调。 这种功能障碍会导致学习、记忆和其他认知缺陷，这是 AD 的核心特征。