Nr4a2 blocks oAbeta-mediated synaptic plasticity dysfunction and ameliorates spatial memory deficits in the APPSw,Ind mouse

Abstract

Alzheimers disease AD is associated with disruptions in neuronal communication, especially in brain regions crucial for learning and memory, such as the hippocampus. The amyloid hypothesis suggests that the accumulation of amyloid-beta oligomers (oA{beta}) contributes to synaptic dysfunction by internalisation of synaptic AMPA receptors. Recently, it has been reported that Nr4a2, a member of the Nr4a family of orphan nuclear receptors, plays a role in hippocampal synaptic plasticity by regulating BDNF and synaptic AMPA receptors. Here, we demonstrate that oA{beta} inhibits activity-dependent Nr4a2 activation in hippocampal neurons, indicating a potential link between oA{beta} and Nr4a2 down-regulation. Furthermore, we have observed a reduction in Nr4a2 protein levels in postmortem hippocampal tissue samples from early AD stages. Pharmacological activation of Nr4a2 proves effective in preventing oA{beta}-mediated synaptic depression in the hippocampus. Notably, Nr4a2 overexpression in the hippocampus of AD mouse models ameliorates spatial learning and memory deficits. In conclusion, the findings suggest that oA{beta} may contribute to early cognitive impairment in AD by blocking Nr4a2 activation, leading to synaptic dysfunction. Thus, our results further support that Nr4a2 activation is a potential therapeutic target to mitigate oA{beta}-induced synaptic and cognitive impairments in the early stages of Alzheimers disease.