Amyloid-beta peptide decreases glutamate uptake in cultured astrocytes: Involvement of oxidative stress and mitogen-activated protein kinase cascades

摘要: Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by excessive deposition of amyloid-beta (Abeta) peptides in the brain. One earliest neuropathological changes AD presence high number reactive astrocytes at sites Abeta deposition. Disturbance glutamatergic neurotransmission and consequent excitotoxicity also believed as implicated progression this dementia. Therefore, study astrocyte responses to Abeta, main cellular type involved maintenance synaptic glutamate concentrations, crucial for understanding pathogenesis AD. This aims investigate effect on astrocytic transporters, transporter-1 (GLT-1) glutamate-aspartate transporter (GLAST), their relative participation clearance. In addition we have investigated involvement mitogen-activated protein (MAP) kinases modulation GLT-1 GLAST levels activity putative contribution oxidative stress induced transport function. used primary cultures rat brain exposed synthetic peptides. The data obtained show that Abeta(1-40) peptide decreased astroglial uptake capacity non-competitive mode inhibition, assessed terms tritium radiolabeled d-aspartate (d-[(3)H]aspartate) transport. seemed be more affected than GLAST, both transporters were Abeta(1-40)-treated astrocytes. We demonstrated MAP kinases, extracellular signal-regulated kinase (ERK), p38 c-Jun N-terminal kinase, activated an early phase treatment whole pathways differentially modulated activity/levels. Moreover it was shown may lead impairment observed. Taken together, our results suggest downregulates part mediated differential complex balance between signaling pathways.