Blockade of adenosine A(2A) receptors reverses early spatial memory defects in the APP/PS1 mouse model of Alzheimer's disease by promoting synaptic plasticity of adult-born granule cells.

The over-activation of adenosine A2A receptors (A2AR) is closely implicated in cognitive impairments of Alzheimer's disease (AD). Growing evidence shows that A2AR blockade possesses neuroprotective effects on AD. Spatial navigation impairment is an early manifestation of cognitive deficits in AD. However, whether A2AR blockade can prevent early impairments in spatial cognitive function and the underlying mechanism is still unclear. A transgenic APP/PS1 mouse model of AD amyloidosis was used in this study. Behavioral tests were conducted to observe the protective effects of A2AR blockade on early spatial memory deficits in 4-month old APP/PS1 mice. To investigate the underlying synaptic mechanism of the protective effects of A2AR blockade, we further examined long-term potentiation (LTP) and network excitation/inhibition balance of dentate gyrus (DG) region, which is relevant to unique synaptic functions of immature adult-born granule cells (abGCs). Subsequently, the protective effects of A2AR blockade on dendritic morphology and synaptic plasticity of 6-week-old abGCs was investigated using retrovirus infection and electrophysiological recordings. The molecular mechanisms underlying neuroprotective properties of A2AR blockade on the synaptic plasticity of abGCs were further explored using molecular biology methods. APP/PS1 mice displayed DG-dependent spatial memory deficits at an early stage. Additionally, impaired LTP and an imbalance in network excitation/inhibition were observed in the DG region of APP/PS1 mice, indicating synaptic structural and functional abnormalities of abGCs. A2AR was found to be upregulated in the hippocampus of the APP/PS1 mouse model of AD. Treatment with the selective A2AR antagonist SCH58261 for three weeks significantly ameliorated spatial memory deficits in APP/PS1 mice and markedly restored LTP and network excitation/inhibition balance in the DG region. Moreover, SCH58261 treatment restored dendritic morphology complexity and enhanced synaptic plasticity of abGCs in APP/PS1 mice. Furthermore, SCH58261 treatment alleviated the impairment of synaptic plasticity in abGCs. It achieved this by remodeling the subunit composition of NMDA receptors and increasing the proportion of NR2B receptors in abGCs of APP/PS1 mice. Blockade of A2AR improves early spatial memory deficits in APP/PS1 mice, possibly by reversing synaptic defects of abGCs. This finding suggests that A2AR blockade could be a potential therapy for AD.

Ji Q ，Yang Y ，Xiong Y ，Zhang YJ ，Jiang J ，Zhou LP ，Du XH ，Wang CX ，Zhu ZR ... -  《Alzheimers Research & Therapy》

Blockade of adenosine A(2A) receptors recovers early deficits of memory and plasticity in the triple transgenic mouse model of Alzheimer's disease.

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.

Silva AC ，Lemos C ，Gonçalves FQ ，Pliássova AV ，Machado NJ ，Silva HB ，Canas PM ，Cunha RA ，Lopes JP ，Agostinho P ... -  《-》

Early synaptic deficits in the APP/PS1 mouse model of Alzheimer's disease involve neuronal adenosine A2A receptors.

Viana da Silva S ，Haberl MG ，Zhang P ，Bethge P ，Lemos C ，Gonçalves N ，Gorlewicz A ，Malezieux M ，Gonçalves FQ ，Grosjean N ，Blanchet C ，Frick A ，Nägerl UV ，Cunha RA ，Mulle C ... -  《Nature Communications》

Adenosine Augmentation Evoked by an ENT1 Inhibitor Improves Memory Impairment and Neuronal Plasticity in the APP/PS1 Mouse Model of Alzheimer's Disease.

Lee CC ，Chang CP ，Lin CJ ，Lai HL ，Kao YH ，Cheng SJ ，Chen HM ，Liao YP ，Faivre E ，Buée L ，Blum D ，Fang JM ，Chern Y ... -  《-》

Adenosine A(2A) Receptor Up-Regulation Pre-Dates Deficits of Synaptic Plasticity and of Memory in Mice Exposed to Aβ(1-42) to Model Early Alzheimer's Disease.

Lopes CR ，Silva AC ，Silva HB ，Canas PM ，Agostinho P ，Cunha RA ，Lopes JP ... -  《Biomolecules》