Research ArticleNeuroscience

Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer’s disease

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Science Signaling  02 Feb 2021:
Vol. 14, Issue 668, eabc5429
DOI: 10.1126/scisignal.abc5429

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Restoring protein synthesis and cognition

The loss of protein synthesis caused by chronic activation of the integrated stress response (ISR) is observed in hippocampal neurons and correlates with cognitive loss in mouse models of Alzheimer’s disease. The compound ISRIB blocks the translation inhibition arm of the ISR but failed to confer cognitive benefit and caused mortality in mouse models of Alzheimer’s disease in previous studies. However, Oliveira et al. found that daily systemic administration of low-dose ISRIB, which did not cause mortality or obvious side effects, rescued protein synthesis and synaptic plasticity in the hippocampus and restored performance on long-term memory tests both in wild-type mice in which translation had been pharmacologically inhibited and in two mouse models of Alzheimer’s disease, although there was no effect on amyloid plaque load. The findings suggest that restoring protein synthesis in the brain may delay cognitive deficits in Alzheimer’s disease patients.

Abstract

Neuronal protein synthesis is essential for long-term memory consolidation, and its dysregulation is implicated in various neurodegenerative disorders, including Alzheimer’s disease (AD). Cellular stress triggers the activation of protein kinases that converge on the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which attenuates mRNA translation. This translational inhibition is one aspect of the integrated stress response (ISR). We found that postmortem brain tissue from AD patients showed increased phosphorylation of eIF2α and reduced abundance of eIF2B, another key component of the translation initiation complex. Systemic administration of the small-molecule compound ISRIB (which blocks the ISR downstream of phosphorylated eIF2α) rescued protein synthesis in the hippocampus, measures of synaptic plasticity, and performance on memory-associated behavior tests in wild-type mice cotreated with salubrinal (which inhibits translation by inducing eIF2α phosphorylation) and in both β-amyloid-treated and transgenic AD model mice. Thus, attenuating the ISR downstream of phosphorylated eIF2α may restore hippocampal protein synthesis and delay cognitive decline in AD patients.

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