Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive decline of memory and cognitive function. The disease is characterized by the presence of amyloid plaques, tau tangles, altered inflammatory signaling, and alterations in numerous neurotransmitter signaling systems, including γ-aminobutyric acid (GABA). Given the extensive role of GABA in regulating neuronal activity, a careful investigation of GABA-related changes is needed. Further, given persistent inflammation has been demonstrated to drive AD pathology, the presence of GABA B receptor expressed on glia that serve a role regulation of the immune response adds to potential implications of altered GABA in AD. There has not previously been a systematic evaluation of GABA-related changes in an amyloid model of AD that specifically focuses on examining changes in GABA B receptors. In the present study, we examined alterations in several GABA-specific targets in the APP/PS1 mouse model at different ages. In the 4-month-old cohort, no significant deficits in spatial learning and memory or alterations in any of the GABAergic targets were observed compared with wild-type controls. However, we identified significant alterations in several GABA-related targets in the 6-month-old cohort that exhibited spatial learning deficits that include changes in glutamic acid decarboxylase 65, GABA transporter type 3, and GABA B receptors protein and mRNA levels. This was the same cohort at which learning and memory deficits and significant amyloid pathology was observed. Overall, our study provides evidence of altered GABAergic signaling in an amyloid model of AD at a time point consistent with AD-related deficits.

中文翻译：

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阿尔茨海默病 APP/PS1 小鼠模型中 GABA B 受体的变化

阿尔茨海默病 (AD) 是一种以记忆和认知功能进行性衰退为特征的神经退行性疾病。该疾病的特征是存在淀粉样蛋白斑块、tau 蛋白缠结、炎症信号改变以及包括 γ-氨基丁酸 (GABA) 在内的许多神经递质信号系统发生改变。鉴于 GABA 在调节神经元活动中的广泛作用，需要仔细研究 GABA 相关的变化。此外，鉴于持续性炎症已被证明会驱动 AD 病理，神经胶质细胞上表达的 GABA B 受体的存在可起到调节免疫反应的作用，这增加了 AD 中 GABA 改变的潜在影响。以前没有对 AD 淀粉样蛋白模型中 GABA 相关变化的系统评估，该模型特别侧重于检查 GABA B 受体的变化。在本研究中，我们检查了不同年龄的 APP/PS1 小鼠模型中几个 GABA 特异性靶标的变化。在 4 个月大的队列中，与野生型对照相比，未观察到空间学习和记忆的显着缺陷或任何 GABA 能目标的改变。然而，我们在 6 个月大的队列中发现了几个 GABA 相关目标的显着变化，这些目标表现出空间学习缺陷，包括谷氨酸脱羧酶 65、GABA 转运蛋白 3 型和 GABA B 受体蛋白和 mRNA 水平的变化。这是观察到学习和记忆缺陷以及显着的淀粉样蛋白病理学的同一队列。