Affiliations: [a] CNC -Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal | [b] Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Correspondence:
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Correspondence to: Paula Agostinho, Center for Neuroscience and Cell Biology, Faculty of Medicine (Polo I), University of Coimbra, Coimbra 3004-517, Portugal. Tel.: +351 239820190; Fax: +351 239822776; E-mails: [email protected] or [email protected].
Abstract: Alzheimer's disease (AD) is characterized by a progressive cognitive impairment tightly correlated with the accumulation of amyloid-β (Aβ) peptides (mainly Aβ1-42). There is a precocious disruption of glutamatergic synapses in AD, in line with an ability of Aβ to decrease astrocytic glutamate uptake. Accumulating evidence indicates that caffeine prevents the burden of AD, likely through the antagonism of A2A receptors (A2AR) which attenuates Aβ-induced memory impairment and synaptotoxicity. Since A2AR also modulate astrocytic glutamate uptake, we now tested if A2AR blockade could prevent the decrease of astrocytic glutamate uptake caused by Aβ. In cultured astrocytes, Aβ1-42 (1 μM for 24 hours) triggered an astrogliosis typified by an increased density of GFAP, which was mimicked by the A2AR agonist, CGS 26180 (30 nM), and prevented by the A2AR antagonist, SCH 58261 (100 nM). Aβ1-42 also decreased D-aspartate uptake by 28 ± 4%, an effect abrogated upon genetic inactivation or pharmacological blockade of A2AR. In accordance with the long term control of glutamate transporter expression by A2AR, Aβ1-42 enhanced the expression and density of astrocytic A2AR and decreased GLAST and GLT-I expression in astrocytes from wild type, but not from A2AR knockout mice. This impact of Aβ1-42 on glutamate transporters and uptake, dependent on A2AR function, was also confirmed in an ex vivo astrocyte preparation (gliosomes) from rats intracerebroventricularly (icv) injected with Aβ1-42. These results provide the first demonstration for a direct key role of astrocytic A2AR in the ability of Aβ-induced impairment of glutamate uptake, which may underlie glutamatergic synaptic dysfunction and excitotoxicity in AD.
