Blockade of adenosine A
2A receptors recovers early deficits of memory and plasticity in the triple transgenic mouse model of Alzheimer’s disease
Neurobiology of Disease. 2018-09-01; 117: 72-81
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Silva AC(1), Lemos C(1), Gonçalves FQ(1), Pliássova AV(1), Machado NJ(1), Silva HB(1), Canas PM(1), Cunha RA(2), Lopes JP(1), Agostinho P(3).
(1)CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
(2)CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Portugal. Electronic address:
(3)CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Portugal.
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.