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Cited by 78Alzheimer's disease research and treatmentsGenetics and Neurodevelopmental DisordersDementia and Cognitive Impairment Research

Alzheimer’s disease-related dysregulation of mRNA translation causes key pathological features with ageing

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Ghosh, Anshua, Mizuno, Keiko, Tiwari, Sachin S., Proitsi, Petroula, Gomez Perez-Nievas, Beatriz, Glennon, Elizabeth, Martinez-Nunez, Rocio T., Giese, K. Peter·2020·Translational Psychiatry
DOI 10.1038/s41398-020-00882-7PMC PMC7297996

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Abstract

Alzheimer’s disease (AD) is characterised by Aβ and tau pathology as well as synaptic degeneration, which correlates best with cognitive impairment. Previous work suggested that this pathological complexity may result from changes in mRNA translation. Here, we studied whether mRNA translation and its underlying signalling are altered in an early model of AD, and whether modelling this deficiency in mice causes pathological features with ageing. Using an unbiased screen, we show that exposure of primary neurons to nanomolar amounts of Aβ increases FMRP-regulated protein synthesis. This selective regulation of mRNA translation is dependent on a signalling cascade involving MAPK-interacting kinase 1 (Mnk1) and the eukaryotic initiation factor 4E (eIF4E), and ultimately results in reduction of CYFIP2, an FMRP-binding protein. Modelling this CYFIP2 reduction in mice, we find age-dependent Aβ accumulation in the thalamus, development of tau pathology in entorhinal cortex and hippocampus, as well as gliosis and synapse loss in the hippocampus, together with deficits in memory formation. Therefore, we conclude that early stages of AD involve increased translation of specific CYFIP2/FMRP-regulated transcripts. Since reducing endogenous CYFIP2 expression is sufficient to cause key features of AD with ageing in mice, we suggest that prolonged activation of this pathway is a primary step toward AD pathology, highlighting a novel direction for therapeutic targeting.

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  • Several AD-like pathologies, including Aβ accumulation, tau hyperphosphorylation, gliosis, and dendritic spine loss in the hippocampus, have been observed in heterozygous Cyfip2 knockout mice but not in mice with a neuron-specific conditional knockout of Cyfip2.

    “Several AD-like pathologies, including Aβ accumulation, tau hyperphosphorylation, gliosis and dendritic spine loss in the hippocampus, have been observed in heterozygous Cyfip2 KO mice153,155 but not in mice with a neuron-specific conditional KO of Cyfip2156.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [155]

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Authors
Ghosh, A., Mizuno, K., Tiwari, S. S., Proitsi, P., Gomez Perez-Nievas, B., Glennon, E., Martinez-Nunez, R. T., & Giese, K. P.
Affiliations
King's College London (GB)
Corresponding author
Giese, K. Peter
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2020-06-16
Volume
10
Issue
1
Pages
192-192
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-020-00882-7
PMC
PMC7297996
OpenAlex
W3035497627
Cited by
78
References
17
Citations by year
2026: 10 · 2025: 12 · 2024: 21 · 2023: 12 · 2022: 13 · 2021: 5 · 2020: 5
FWCI
5.25
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (submittedVersion, other-oa)
Funders
  • RCUK | Medical Research Council (PhD studentship)
  • Alzheimer's Research UK (pump priming grant)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, mRNA translation, FMRP, CYFIP2, MNK1, eIF4E, amyloid-beta, tau pathology, synaptic degeneration, gliosis, memory impairment, aging, thalamus, hippocampus, entorhinal cortex, translational regulation
MeSH terms
Aging, Alzheimer Disease, Animals, Mice, Transgenic, Neurons, Synapses, Protein Biosynthesis, Amyloid beta-Peptides, tau Proteins, Adaptor Proteins, Signal Transducing, Mice

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