Genetic Reduction of the Translational Repressors <scp>FMRP</scp> and <scp>4E</scp> ‐ <scp>BP2</scp> Preserves Memory in Mouse Models of Alzheimer's Disease
Alzheimer's disease (AD) is characterized by progressive memory decline. Converging evidence indicates that hippocampal mRNA translation (protein synthesis) is defective in AD. Here, we show that genetic reduction of the translational repressors, Fragile X messenger ribonucleoprotein (FMRP) or eukaryotic initiation factor 4E (eIF4E)-binding protein 2 (4E-BP2), prevented the attenuation of hippocampal protein synthesis and memory impairment induced by AD-linked amyloid-β oligomers (AβOs) in mice. Moreover, genetic reduction of 4E-BP2 rescued memory deficits in aged APPswe/PS1dE9 (APP/PS1) transgenic mouse model of AD. Our findings demonstrate that strategies targeting repressors of mRNA translation correct hippocampal protein synthesis and memory deficits in AD models. Results suggest that modulating pathways controlling brain mRNA translation may confer memory benefits in AD.
Authors
- Argel Aguilar‐Valles (ORCID: https://orcid.org/0000-0002-2272-1138)
- Nahum Sonenberg (ORCID: https://orcid.org/0000-0002-4707-8759)
- Brandon Rodrigue
- Felipe C. Ribeiro (ORCID: https://orcid.org/0000-0003-3028-3307)
- Fernanda G. De Felice (ORCID: https://orcid.org/0000-0001-8358-0589)
- Mychael V. Lourenco (ORCID: https://orcid.org/0000-0002-1078-0296)
- Jean‐Claude Lacaille (ORCID: https://orcid.org/0000-0003-4056-0574)
- Danielle Cozachenco (ORCID: https://orcid.org/0000-0002-2258-8314)
- Karim Nader (ORCID: https://orcid.org/0000-0003-3571-1796)
- Sérgio T. Ferreira (ORCID: https://orcid.org/0000-0001-7160-9866)
- Cristiano Piacsek Borges (ORCID: https://orcid.org/0000-0002-9598-7877)
- Michael Parkhill
Institutions
- Universidade Federal do Rio de Janeiro (BR)
- Universidade Estadual de Campinas (UNICAMP) (BR)
- Queen's University (CA)
- Centre for Research on Brain Language and Music (CA)
- D’Or Institute for Research and Education (BR)
- Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (BR)
- McGill University (CA)
- Carleton University (CA)
Publication Details
- Journal
- Aging Cell
- Published
- 2025-12-03
- DOI
- https://doi.org/10.1111/acel.70315
- Primary Topic
- Genetics and Neurodevelopmental Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Alzheimer's Association
- American Society for Biochemistry and Molecular Biology
- Alzheimer's Society
- Company of Biologists
- International Brain Research Organization
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro
- Instituto Nacional de Ciência e Tecnologia de Neurociência Translacional
- International Society for Neurochemistry
- Instituto Serrapilheira