AMYLOID-BETA PEPTIDE DECREASES GLUTAMATE UPTAKE IN CULTURED ASTROCYTES: INVOLVEMENT OF OXIDATIVE STRESS AND MITOGEN-ACTIVATED PROTEIN KINASE CASCADES
AMYLOID-BETA PEPTIDE DECREASES GLUTAMATE UPTAKE IN CULTURED ASTROCYTES: INVOLVEMENT OF OXIDATIVE STRESS AND MITOGEN-ACTIVATED PROTEIN KINASE CASCADES
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DOI：
10.1016/j.neuroscience.2008.08.022
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发表时间：
2008-10-28
期刊：
影响因子：
3.3
通讯作者：
Agostinho, P.
中科院分区：
文献类型：
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作者：
Matos, M.;Augusto, E.;Agostinho, P.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，主要特征是大脑中淀粉样蛋白（a β）肽的过度沉积。阿尔茨海默病最早的神经病理改变之一是a β沉积部位出现大量反应性星形胶质细胞。谷氨酸能神经传递紊乱和随之而来的兴奋性毒性也被认为与这种痴呆的进展有关。因此，研究星形胶质细胞对参与维持突触谷氨酸浓度的主要细胞类型A β的反应，对于了解AD的发病机制至关重要。本研究旨在探讨A β对星形胶质细胞谷氨酸转运体谷氨酸转运体-1 （GLT-1）和谷氨酸-天冬氨酸转运体（GLAST）的影响及其在谷氨酸清除中的作用。此外，我们还研究了丝裂原活化蛋白（MAP）激酶参与GLT-11和GLAST水平和活性的调节，以及A β诱导的氧化应激对星形细胞谷氨酸转运功能的可能贡献。因此，我们使用暴露于AV合成肽的大鼠脑星形胶质细胞的原代培养。获得的数据表明，β(1-40)肽以非竞争性抑制模式降低星形胶质细胞谷氨酸摄取能力，以氚放射性标记的D-天冬氨酸（D-[H-3]天冬氨酸）运输来评估。在A β(1-40)处理的星形胶质细胞中，GLT-1的活性似乎比GLAST的活性受到更大的影响，两种转运蛋白的水平均下降。我们证明MAP激酶、细胞外信号调节激酶（ERK）、p38和c-Jun n末端激酶在A β(1-40)治疗的早期阶段被激活，并且整个途径对谷氨酸转运蛋白活性/lev-有差异调节
Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by excessive deposition of amyloid-beta (A beta) peptides in the brain. One of the earliest neuropathological changes in AD is the presence of a high number of reactive astrocytes at sites of A beta deposition. Disturbance of glutamatergic neurotransmission and consequent excitotoxicity is also believed as implicated in the progression of this dementia. Therefore, the study of astrocyte responses to A beta, the main cellular type involved in the maintenance of synaptic glutamate concentrations, is crucial for understanding the pathogenesis of AD. This study aims to investigate the effect of A beta on the astrocytic glutamate transporters, glutamate transporter-1 (GLT-1) and glutamate-aspartate transporter (GLAST), and their relative participation to glutamate clearance. In addition we have also investigated the involvement of mitogen-activated protein (MAP) kinases in the modulation of GLT-11 and GLAST levels and activity and the putative contribution of oxidative stress induced by A beta to the astrocytic glutamate transport function. Therefore, we used primary cultures of rat brain astrocytes exposed to AV synthetic peptides. The data obtained show that A beta(1-40) peptide decreased astroglial glutamate uptake capacity in a non-competitive mode of inhibition, assessed in terms of tritium radiolabeled D-aspartate (D-[H-3]aspartate) transport. The activity of GLT-1 seemed to be more affected than that of GLAST, and the levels of both transporters were decreased in A beta(1-40)-treated astrocytes. We demonstrated that MAP kinases, extracellular signal-regulated kinase (ERK), p38 and c-Jun N-terminal kinase, were activated in an early phase of A beta(1-40) treatment and the whole pathways differentially modulated the glutamate transporters activity/lev-