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Synaptic and memory dysfunction in a β-amyloid model of early Alzheimer's disease depends on increased formation of ATP-derived extracellular adenosine

Gonçalves, Francisco Q. ; Lopes, João P. ; Silva, Henrique B. ; Lemos, Cristina ; Silva, António C. ; Gonçalves, Nélio ; Tomé, Ângelo R. ; Ferreira, Samira G. ; Canas, Paula M. ; Rial, Daniel ; Agostinho, Paula ; Cunha, Rodrigo A.

Neurobiology of disease, 2019-12, Vol.132, p.104570-104570, Article 104570 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Synaptic and memory dysfunction in a β-amyloid model of early Alzheimer's disease depends on increased formation of ATP-derived extracellular adenosine
Autor: Gonçalves, Francisco Q. ; Lopes, João P. ; Silva, Henrique B. ; Lemos, Cristina ; Silva, António C. ; Gonçalves, Nélio ; Tomé, Ângelo R. ; Ferreira, Samira G. ; Canas, Paula M. ; Rial, Daniel ; Agostinho, Paula ; Cunha, Rodrigo A.
Assuntos: 5'-Nucleotidase - metabolism ; Adenosine - metabolism ; Adenosine Triphosphate - metabolism ; Alzheimer Disease - metabolism ; Animals ; Disease Models, Animal ; Hippocampus - metabolism ; Long-Term Potentiation - physiology ; Male ; Maze Learning - physiology ; Memory Disorders - metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Receptor, Adenosine A2A - metabolism
É parte de: Neurobiology of disease, 2019-12, Vol.132, p.104570-104570, Article 104570
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SourceType-Scholarly Journals-1
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Descrição: Adenosine A2A receptors (A2AR) overfunction causes synaptic and memory dysfunction in early Alzheimer's disease (AD). In a β-amyloid (Aβ1-42)-based model of early AD, we now unraveled that this involves an increased synaptic release of ATP coupled to an increased density and activity of ecto-5′-nucleotidase (CD73)-mediated formation of adenosine selectively activating A2AR. Thus, CD73 inhibition with α,β-methylene-ADP impaired long-term potentiation (LTP) in mouse hippocampal slices, which is occluded upon previous superfusion with the A2AR antagonist SCH58261. Furthermore, α,β-methylene-ADP did not alter LTP amplitude in global A2AR knockout (KO) and in forebrain neuron-selective A2AR-KO mice, but inhibited LTP amplitude in astrocyte-selective A2AR-KO mice; this shows that CD73-derived adenosine solely acts on neuronal A2AR. In agreement with the concept that ATP is a danger signal in the brain, ATP release from nerve terminals is increased after intracerebroventricular Aβ1-42 administration, together with CD73 and A2AR upregulation in hippocampal synapses. Importantly, this increased CD73 activity is critically required for Aβ1-42 to impair synaptic plasticity and memory since Aβ1-42-induced synaptic and memory deficits were eliminated in CD73-KO mice. These observations establish a key regulatory role of CD73 activity over neuronal A2AR and imply CD73 as a novel target for modulation of early AD. •A2AR-mediated control of LTP requires CD73-mediated catabolism into adenosine.•β-amyloid caused synaptic and memory dysfunction involving CD73/A2AR upregulation.•A2AR overfunction needs increased ATP release and CD73-convertion to adenosine.•CD73 is a key controller of A2AR and a novel target to interfere with AD.
Editor: United States: Elsevier Inc
Idioma: Inglês

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Synaptic and memory dysfunction in a β-amyloid model of early Alzheimer's disease depends on increased formation of ATP-derived extracellular adenosine

Gonçalves, Francisco Q. ; Lopes, João P. ; Silva, Henrique B. ; Lemos, Cristina ; Silva, António C. ; Gonçalves, Nélio ; Tomé, Ângelo R. ; Ferreira, Samira G. ; Canas, Paula M. ; Rial, Daniel ; Agostinho, Paula ; Cunha, Rodrigo A.

United States: Elsevier Inc

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