Attenuation of translational repression rescues memory impairment in Alzheimer`s disease mice

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is characterized by impaired synaptic plasticity and progressive memory deficits. Converging evidence indicates that hippocampal mRNA translation, required for memory consolidation, is defective in AD. Eukaryotic initiation factor 4E (eIF4E)‐binding protein 2 (4E‐BP2) and Fragile X mental retardation protein (FMRP) act as translational brakes at different stages of protein synthesis. While 4E‐BP2 represses protein synthesis at the initiation step through inhibition of ribosome‐mRNA complex formation, FMRP blocks translation at the mRNA elongation step through ribosome stallingMethodAβ oligomers were injected in 3‐month old mice lacking one allele of 4E‐BP2 and one or two alleles of Fmr1. Protein synthesis was assessed by non‐radioactive incorporation of puromycin (SuNSET) in hippocampal slices. Memory performance was assessed by contextual fear conditioning (CFC). Moreover, mice lacking one allele of 4E‐BP2 were crossed with APP/PS1 mice and memory was assessed by CFC at 12 month old.ResultGenetic reduction of the translational repressors FMRP or 4E‐BP2, prevented the inhibition of hippocampal protein synthesis and memory impairment induced by Alzheimer’s‐linked amyloid‐β oligomers (AβOs) in mice. Moreover, 4E‐BP2 deletion rescued memory deficits in the APPswe/PS1dE9 (APP/PS1) transgenic mouse model of ADConclusionOur findings demonstrate that strategies targeting translational repression correct hippocampal protein synthesis and memory deficits in AD models.