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. 2018 Sep;117:72-81.
doi: 10.1016/j.nbd.2018.05.024. Epub 2018 May 31.

Blockade of Adenosine A 2A Receptors Recovers Early Deficits of Memory and Plasticity in the Triple Transgenic Mouse Model of Alzheimer's Disease

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Blockade of Adenosine A 2A Receptors Recovers Early Deficits of Memory and Plasticity in the Triple Transgenic Mouse Model of Alzheimer's Disease

António C Silva et al. Neurobiol Dis. .

Abstract

Alzheimer's disease (AD) begins with a deficit of synaptic function and adenosine A2A receptors (A2AR) are mostly located in synapses controlling synaptic plasticity. The over-activation of adenosine A2A receptors (A2AR) causes memory deficits and the blockade of A2AR prevents memory damage in AD models. We now enquired if this prophylactic role of A2AR 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 A2AR in the hippocampus (130 ± 22%). After the onset of memory deficits in 3xTg-AD mice, a three weeks treatment with the selective A2AR antagonist normalized the up-regulation of hippocampal A2AR 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 A2AR 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.

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