RESUMO
Synaptic dysfunction is an early event in the development of Alzheimer's disease (AD) and relates closely to the cognitive impairment characterizing this neurodegenerative process. A causative association has been proposed, largely on the basis of in vitro studies, between memory decline, soluble amyloid-ß (Aß) oligomers and alterations of glutamatergic neurotransmission. We aimed here to characterize in vivo N-methyl-D-aspartate receptor (NMDAR)-mediated signaling, at an early stage of AD, before extracellular amyloid plaques are deposited. We assessed the functional link between cognitive abilities and NMDAR-mediated pharmacological responses of six-month-old AßPP23 transgenic mice (AßPP23tg), overexpressing the human amyloid-ß protein precursor carrying the Swedish double mutation. We found evidence of cognitive impairments in these mice, indicated by deficits in the delayed-non-matching-to-place task. Alterations of NMDAR-mediated signaling in this mouse model were confirmed by the reduced sensitivity of motor-activation and working memory to pharmacological inhibition of NMDAR activity. At the molecular level, AßPP23tg mice show hippocampal alterations in the trafficking of synaptic NMDAR subunits NR2A and NR2B and at an ultrastructural analysis show Aß oligomers intracellularly localized in the synaptic compartments. Importantly, the behavioral and biochemical alterations of NMDAR signaling are associated with the inhibition of long-term synaptic potentiation and inversion of metaplasticity at CA1 synapses in hippocampal slices from AßPP23tg mice. These results indicate a general impairment of synaptic function and learning and memory in young AßPP23tg mice with Aß oligomers but no amyloid plaques.
