Autor(es):
Silva, Sílvia Viana da ; Haberl, Matthias Georg ; Zhang, Pei ; Bethge, Philipp ; Lemos, Cristina ; Gonçalves, Nélio ; Gorlewicz, Adam ; Malezieux, Meryl ; Gonçalves, Francisco Q. ; Grosjean, Noëlle ; Blanchet, Christophe ; Frick, Andreas ; Nägerl, U Valentin ; Cunha, Rodrigo A. ; Mulle, Christophe
Data: 2016
Identificador Persistente: https://hdl.handle.net/10316/108713
Origem: Estudo Geral - Universidade de Coimbra
Assunto(s): Adenosine A2 Receptor Antagonists; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; CA3 Region, Hippocampal; Dendritic Spines; Disease Models, Animal; Gene Expression Regulation; Humans; Long-Term Potentiation; Memory, Episodic; Mice; Mice, Transgenic; Neuroprotective Agents; Presenilin-1; Pyrimidines; RNA, Small Interfering; Receptor, Adenosine A2A; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Synapses; Triazines; Triazoles
Descrição
Synaptic plasticity in the autoassociative network of recurrent connections among hippocampal CA3 pyramidal cells is thought to enable the storage of episodic memory. Impaired episodic memory is an early manifestation of cognitive deficits in Alzheimer's disease (AD). In the APP/PS1 mouse model of AD amyloidosis, we show that associative long-term synaptic potentiation (LTP) is abolished in CA3 pyramidal cells at an early stage. This is caused by activation of upregulated neuronal adenosine A2A receptors (A2AR) rather than by dysregulation of NMDAR signalling or altered dendritic spine morphology. Neutralization of A2AR by acute pharmacological inhibition, or downregulation driven by shRNA interference in a single postsynaptic neuron restore associative CA3 LTP. Accordingly, treatment with A2AR antagonists reverts one-trial memory deficits. These results provide mechanistic support to encourage testing the therapeutic efficacy of A2AR antagonists in early AD patients.
