Astrocytic Adenosine A 2A Receptors Control the Amyloid-β Peptide-Induced Decrease of Glutamate Uptake

Abstract

Alzheimer's disease (AD) is characterized by a progressive cognitive impairment tightly correlated with the accumulation of amyloid-β (Aβ) peptides (mainly Aβ_1-42). 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 A_2A receptors (A_2AR) which attenuates Aβ-induced memory impairment and synaptotoxicity. Since A_2AR also modulate astrocytic glutamate uptake, we now tested if A_2AR blockade could prevent the decrease of astrocytic glutamate uptake caused by Aβ. In cultured astrocytes, Aβ_1-42 (1 μM for 24 hours) triggered an astrogliosis typified by an increased density of GFAP, which was mimicked by the A_2AR agonist, CGS 26180 (30 nM), and prevented by the A_2AR antagonist, SCH 58261 (100 nM). Aβ_1-42 also decreased D-aspartate uptake by 28 ± 4%, an effect abrogated upon genetic inactivation or pharmacological blockade of A_2AR. In accordance with the long term control of glutamate transporter expression by A_2AR, Aβ_1-42 enhanced the expression and density of astrocytic A_2AR and decreased GLAST and GLT-I expression in astrocytes from wild type, but not from A_2AR knockout mice. This impact of Aβ_1-42 on glutamate transporters and uptake, dependent on A_2AR function, was also confirmed in an ex vivo astrocyte preparation (gliosomes) from rats intracerebroventricularly (icv) injected with Aβ_1-42. These results provide the first demonstration for a direct key role of astrocytic A_2AR in the ability of Aβ-induced impairment of glutamate uptake, which may underlie glutamatergic synaptic dysfunction and excitotoxicity in AD.