Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer’s disease
Top Cited Papers
- 2 February 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Signaling
- Vol. 14 (668)
- https://doi.org/10.1126/scisignal.abc5429
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.Keywords
Funding Information
- National Institutes of Health (NS034007)
- National Institutes of Health (AG04469)
- National Institutes of Health (AG055581)
- National Institutes of Health (AG056622)
- Alzheimer’s Association (AARG-D-615741)
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (406436/2016-9)
- Programa de Apoyo a Centros con Financiamiento Basal to Fundación Ciencia & Vida (AFB 170004)
- Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (201.432/2014)
- International Society for Neurochemistry (CAEN 1A)
- Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (202.817/2016)
- International Society for Neurochemistry (CAEN 1B)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (434093/2018-1)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (473324/2013-0)
- Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (202.944/2015)
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