星形胶质细胞功能障碍改变链脲佐菌素诱导的散发性阿尔茨海默病模型中gaba能通讯和氨代谢。

IF 2.8 Q2 NEUROSCIENCES
Journal of Alzheimer's disease reports Pub Date : 2024-10-18 eCollection Date: 2024-01-01 DOI:10.1177/25424823241289036
Éverton Carlos Brezolin, Vitor Gayger-Dias, Vanessa-Fernanda Da Silva, Anderson Cigerce, Bruna Schultz, Thomas Michel Sobottka, Patrícia Nardin, Adriano Martimbianco de Assis, Marina Concli Leite, André Quincozes-Santos, Larissa Daniele Bobermin, Carlos-Alberto Gonçalves
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引用次数: 0

摘要

背景:在脑室注射链脲佐菌素(STZ)诱导的散发性阿尔茨海默病(AD)模型中,认知障碍伴随着淀粉样蛋白沉积前海马特异性星形细胞改变。目的:假设GABA的合成通过MAO-B导致氨升高,从而损害抗氧化防御和ATP合成,并可能导致认知损伤,我们测定了海马中谷氨酰胺合成酶(GS)、单胺氧化酶B (MAO-B)和其他与GABA代谢相关的酶的水平。方法:在stz后4周和16周,在散发性stz诱导AD模型中,分别对应淀粉样蛋白前期和淀粉样蛋白期,对Wistar大鼠海马标本进行免疫印迹和RT-PCR检测。结果:在第4周和第16周,我们观察到GS活性降低,MAO-B含量增加,这加强了星形胶质细胞功能障碍在淀粉样蛋白期之前的观点。这些变化伴随着鸟氨酸脱羧酶1 (ODC1)含量的增加,该酶催化腐胺的合成(通过MAO-B合成GABA的底物),精氨酸-甘氨酸氨基转移酶(AGAT)基因表达的减少,AGAT是一种参与肌酸合成的酶,并参与GABA激动剂的产生。这些变化只出现在AD模型的淀粉样蛋白阶段。结论:我们的发现有助于解释在这一阶段发生的更大的能量代谢损伤,以及更大的gaba能损失。这些变化加强了STZ模型的重要性,并进一步加深了我们对AD两个阶段变化的理解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Astrocyte dysfunction alters GABAergic communication and ammonia metabolism in the streptozotocin-induced sporadic Alzheimer's disease model.

Background: In the sporadic model of Alzheimer's disease (AD), induced by intracerebroventricular streptozotocin (STZ) administration, cognitive impairment is accompanied by specific astrocytic changes in the hippocampus prior to amyloid deposition.

Objective: Hypothesizing that the synthesis of GABA, via MAO-B, contributes to ammonia elevation, thereby compromising antioxidant defense and ATP synthesis, and possibly contributing to cognitive damage, we determined the hippocampal levels of glutamine synthetase (GS), monoamine oxidase B (MAO-B) and other enzymes related to GABA metabolism.

Methods: Immunoblotting and RT-PCR assays were carried out in hippocampal samples of Wistar rats, at 4 and 16 weeks post-STZ, in the sporadic STZ-induced AD model, corresponding to the pre-amyloid and amyloid phases, respectively.

Results: We observed a reduction in GS activity and increased MAO-B content, both in 4 weeks and in 16 weeks, reinforcing the idea that astroglial dysfunction precedes the amyloid phase. These alterations were accompanied by an increase in the content of ornithine decarboxylase 1 (ODC1), which catalyzes the synthesis of putrescine (substrate for GABA synthesis, via MAO-B), and a reduction in the gene expression of arginine-glycine amidinotransferase (AGAT), an enzyme involved in the synthesis of creatine, and in the generation of GABA agonists. These changes were only seen in the amyloid phase of the AD model.

Conclusions: Our findings contribute to explain the greater damage that occurs in energy metabolism at this stage, in addition to the greater GABAergic loss. The changes reinforce the importance of the STZ model and further our understanding of the changes in both AD phases.

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