Astrocytic Adenosine A2A Receptors Control the Amyloid-ß Peptide-Induced Decrease of Glutamate Uptake
JAD. 2012-08-22; 31(3): 555-567
DOI: 10.3233/jad-2012-120469
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Matos M(1), Augusto E, Machado NJ, dos Santos-Rodrigues A, Cunha RA, Agostinho
P.
Author information:
(1)CNC -Center for Neuroscience and Cell Biology, University of Coimbra,
Coimbra, Portugal.
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(2A)R) which attenuates Aβ-induced memory
impairment and synaptotoxicity. Since A(2A)R also modulate astrocytic glutamate
uptake, we now tested if A(2A)R 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(2A)R agonist, CGS 26180 (30 nM), and prevented
by the A(2A)R 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 A(2A)R. In accordance with the long term control of
glutamate transporter expression by A(2A)R, Aβ(1-42). enhanced the expression
and density of astrocytic A(2A)R and decreased GLAST and GLT-I expression in
astrocytes from wild type, but not from A(2A)R knockout mice. This impact of
Aβ(1-42). on glutamate transporters and uptake, dependent on A(2A)R 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(2A)R in the
ability of Aβ-induced impairment of glutamate uptake, which may underlie
glutamatergic synaptic dysfunction and excitotoxicity in AD.
DOI: 10.3233/JAD-2012-120469
PMID: 22647260 [Indexed for MEDLINE]