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

M. Matos, E. Augusto, C.R. Oliveira, P. Agostinho
Neuroscience. 2008-10-01; 156(4): 898-910
DOI: 10.1016/j.neuroscience.2008.08.022

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Matos M(1), Augusto E, Oliveira CR, Agostinho P.

Author information:
(1)Center for Neuroscience and Cell Biology, Department of Zoology, University
of Coimbra, Coimbra, Portugal.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder primarily
characterized by excessive deposition of amyloid-beta (Abeta) 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 Abeta 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 Abeta, 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 Abeta 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-1 and GLAST
levels and activity and the putative contribution of oxidative stress induced by
Abeta to the astrocytic glutamate transport function. Therefore, we used primary
cultures of rat brain astrocytes exposed to Abeta synthetic peptides. The data
obtained show that Abeta(1-40) peptide decreased astroglial glutamate uptake
capacity in a non-competitive mode of inhibition, assessed in terms of tritium
radiolabeled d-aspartate (d-[(3)H]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 Abeta(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 Abeta(1-40) treatment and
the whole pathways differentially modulated the glutamate transporters
activity/levels. Moreover it was shown that oxidative stress induced by
Abeta(1-40) may lead to the glutamate uptake impairment observed. Taken
together, our results suggest that Abeta peptide downregulates the astrocytic
glutamate uptake capacity and this effect may be in part mediated by oxidative
stress and the differential activity and complex balance between the MAP kinase
signaling pathways.