Department of Neurology & Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232-8552, USA.
Vanderbilt Kennedy Center of Human Development, Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232-8522, USA.
Int J Mol Sci. 2021 Jul 1;22(13):7133. doi: 10.3390/ijms22137133.
Our recent work on genetic epilepsy (GE) has identified common mechanisms between GE and neurodegenerative diseases including Alzheimer's disease (AD). Although both disorders are seemingly unrelated and occur at opposite ends of the age spectrum, it is likely there are shared mechanisms and studies on GE could provide unique insights into AD pathogenesis. Neurodegenerative diseases are typically late-onset disorders, but the underlying pathology may have already occurred long before the clinical symptoms emerge. Pathophysiology in the early phase of these diseases is understudied but critical for developing mechanism-based treatment. In AD, increased seizure susceptibility and silent epileptiform activity due to disrupted excitatory/inhibitory (E/I) balance has been identified much earlier than cognition deficit. Increased epileptiform activity is likely a main pathology in the early phase that directly contributes to impaired cognition. It is an enormous challenge to model the early phase of pathology with conventional AD mouse models due to the chronic disease course, let alone the complex interplay between subclinical nonconvulsive epileptiform activity, AD pathology, and cognition deficit. We have extensively studied GE, especially with gene mutations that affect the GABA pathway such as mutations in GABA receptors and GABA transporter 1. We believe that some mouse models developed for studying GE and insights gained from GE could provide unique opportunity to understand AD. These include the pathology in early phase of AD, endoplasmic reticulum (ER) stress, and E/I imbalance as well as the contribution to cognitive deficit. In this review, we will focus on the overlapping mechanisms between GE and AD, the insights from mutations affecting GABA receptors, and GABA transporter 1. We will detail mechanisms of E/I imbalance and the toxic epileptiform generation in AD, and the complex interplay between ER stress, impaired membrane protein trafficking, and synaptic physiology in both GE and AD.
我们最近在遗传性癫痫（GE）方面的研究工作确定了 GE 与神经退行性疾病（包括阿尔茨海默病（AD））之间的共同机制。尽管这两种疾病看似无关，而且发生在年龄谱的两端，但很可能存在共同的机制，对 GE 的研究可能为 AD 的发病机制提供独特的见解。神经退行性疾病通常是迟发性疾病，但潜在的病理可能早在临床症状出现之前就已经发生了。这些疾病早期的病理生理学研究不足，但对于开发基于机制的治疗方法至关重要。在 AD 中，由于兴奋性/抑制性（E/I）平衡失调导致癫痫易感性和沉默性癫痫样活动增加，比认知缺陷更早被识别出来。增加的癫痫样活动很可能是早期的主要病理，直接导致认知障碍。由于慢性疾病过程，更不用说亚临床非惊厥性癫痫样活动、AD 病理和认知缺陷之间的复杂相互作用，使用传统的 AD 小鼠模型来模拟早期病理是一个巨大的挑战。我们已经广泛研究了 GE，特别是研究了影响 GABA 途径的基因突变，如 GABA 受体和 GABA 转运体 1 的突变。我们相信，一些用于研究 GE 的小鼠模型和从 GE 中获得的见解可能为理解 AD 提供独特的机会。这些包括 AD 早期阶段的病理、内质网（ER）应激和 E/I 失衡以及对认知缺陷的贡献。在这篇综述中，我们将重点介绍 GE 和 AD 之间的重叠机制、影响 GABA 受体和 GABA 转运体 1 的突变的见解。我们将详细介绍 E/I 失衡和 AD 中有毒癫痫样发作的机制，以及 ER 应激、膜蛋白转运受损和两者之间突触生理学的复杂相互作用在 GE 和 AD 中的作用。
