Medical School, Kunming University of Science & Technology, Kunming, Yunnan, 650500, China.
Department of Geriatric Psychiatry, Shenzhen Mental Health Center, Shenzhen Kangning Hospital, Shenzhen, Guangdong, 518020, China.
Neurochem Int. 2024 May;175:105718. doi: 10.1016/j.neuint.2024.105718. Epub 2024 Mar 13.
Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Recent evidence suggests that gamma-aminobutyric acid B (GABA) receptor-mediated inhibition is a major contributor to AD pathobiology, and GABA receptors have been hypothesized to be a potential target for AD treatment. The aim of this study is to determine how GABA regulation alters cognitive function and brain activity in an AD mouse model. Early, middle and late stage (8-23 months) amyloid precursor protein (APP) and presenilin 1 (PS1) transgenic mice were used for the study. The GABA agonist baclofen (1 and 2.5 mg/kg, i. p.) and the antagonist phaclofen (0.5 mg/kg, i. p.) were used. Primarily, we found that GABA activation was able to improve spatial and/or working memory performance in early and late stage AD animals. In addition, GABA activation and inhibition could regulate global and local EEG oscillations in AD animals, with activation mainly regulating low-frequency activity (delta-theta bands) and inhibition mainly regulating mid- and high-frequency activity (alpha-gamma bands), although the regulated magnitude at some frequencies was reduced in AD. The cognitive improvements in AD animals may be explained by the reduced EEG activity in the theta frequency band (2-4 Hz). This study provides evidence for a potential therapeutic effect of baclofen in the elderly AD brain and for GABA receptor-mediated inhibition as a potential therapeutic target for AD.
阿尔茨海默病（AD）是老年人中最常见的痴呆症病因。最近的证据表明，γ-氨基丁酸 B（GABA）受体介导的抑制作用是 AD 病理生物学的主要贡献因素，并且 GABA 受体被假设为 AD 治疗的潜在靶点。本研究旨在确定 GABA 调节如何改变 AD 小鼠模型中的认知功能和大脑活动。使用早期、中期和晚期（8-23 个月）淀粉样前体蛋白（APP）和早老素 1（PS1）转基因小鼠进行研究。使用 GABA 激动剂巴氯芬（1 和 2.5mg/kg，ip）和拮抗剂 phaclofen（0.5mg/kg，ip）。主要发现是，GABA 激活能够改善 AD 动物的空间和/或工作记忆表现，无论是早期还是晚期。此外，GABA 激活和抑制可以调节 AD 动物的全局和局部 EEG 振荡，激活主要调节低频活动（δ-θ 波段），抑制主要调节中频和高频活动（α-γ 波段），尽管在 AD 中一些频率的调节幅度降低。AD 动物的认知改善可以用θ频段（2-4Hz）的 EEG 活动减少来解释。这项研究为巴氯芬在老年 AD 大脑中的潜在治疗效果以及 GABA 受体介导的抑制作用作为 AD 的潜在治疗靶点提供了证据。
