Blockade of adenosine A2A receptors recovers early deficits of memory and plasticity in the triple transgenic mouse model of Alzheimer's disease

Abstract

Alzheimer's disease (AD) begins with a deficit of synaptic function and adenosine A_2A receptors (A_2AR) are mostly located in synapses controlling synaptic plasticity. The over-activation of adenosine A_2A receptors (A_2AR) causes memory deficits and the blockade of A_2AR prevents memory damage in AD models. We now enquired if this prophylactic role of A_2AR might be extended to a therapeutic potential. We used the triple transgenic model of AD (3xTg-AD) and defined that the onset of memory dysfunction occurred at 4 months of age in the absence of locomotor or emotional alterations. At the onset of memory deficits, 3xTg mice displayed a decreased density of markers of excitatory synapses (10.6 ± 3.8% decrease of vGluT1) without neuronal or glial overt damage and an increase of synaptic A_2AR in the hippocampus (130 ± 22%). After the onset of memory deficits in 3xTg-AD mice, a three weeks treatment with the selective A_2AR antagonist normalized the up-regulation of hippocampal A_2AR and restored hippocampal-dependent reference memory, as well as the decrease of hippocampal synaptic plasticity (60.0 ± 3.7% decrease of long-term potentiation amplitude) and the decrease of global (syntaxin-I) and glutamatergic synaptic markers (vGluT1). These findings show a therapeutic-like ability of A_2AR antagonists to recover synaptic and memory dysfunction in early AD.

Keywords: A(2A) receptors; Adenosine; Alzheimer's disease; Hippocampus; LTP; Memory; Synapse; Synaptic plasticity; Vesicular glutamate transporter.