mTOR Hyperactivation in Down Syndrome Hippocampus Appears Early During Development
Abstract
The mammalian target of rapamycin (mTOR) signaling pathway is a key developmental pathway involved in mechanisms underlying cellular aging and neurodegeneration. We hypothesized that its deregulation may occur during early brain development in patients with Down syndrome (DS). The expression patterns and cellular distribution of components of mTOR signaling (phosphorylated S6, phosphorylated S6 kinase, phosphorylated eukaryotic initiation factor 4E binding protein 1, and phosphorylated mTOR) were investigated in developing hippocampi from controls and patients with DS and from adults with DS and Alzheimer disease-associated pathology using immunocytochemistry. In control hippocampi, only phosphorylated S6 was detected prenatally (19-41 gestational weeks); it became undetectable 2 months postnatally. Increased expression of phosphorylated S6, phosphorylated S6 kinase, phosphorylated eukaryotic initiation factor 4E binding protein 1, and phosphorylated mTOR was observed in DS hippocampus compared with controls. Phosphorylated S6 and phosphorylated S6 kinase were detected prenatally and persisted throughout postnatal development. Prominent expression of mTOR components was observed in pyramidal neurons with granulovacuolar degeneration and in neurons containing neurofibrillary tangles in the hippocampi of DS subjects with Alzheimer disease pathology. These findings suggest that a dysregulated mTOR pathway may contribute to both early hippocampal developmental abnormalities and h…
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mTOR activation is abnormally high in the brains of DS mouse models and in DS fibroblasts.
“the abnormally high level of mTOR activation seen in the brains of DS mouse models (Iyer et al., 2014;Perluigi et al., 2014) and in DS fibroblasts (Bordi et al., manuscript submitted)”
From Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99) (2019) · cites this paper as Iyer et al., 2014
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- Authors
- Iyer, A. M., van Scheppingen, J., Milenkovic, I., Anink, J. J., Adle-Biassette, H., Kovacs, G. G., & Aronica, E.
- Affiliations
- Inserm (FR)
- Amsterdam UMC Location University of Amsterdam (NL)
- Corresponding author
- Aronica, Eleonora
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-07
- Volume
- 73
- Issue
- 7
- Pages
- 671-683
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- OpenAlex
- W1986484864
- Cited by
- 69
- References
- 8
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 3 · 2023: 1 · 2022: 5 · 2021: 10 · 2020: 6 · 2019: 7 · 2018: 5 · 2017: 5 · 2016: 9 · 2015: 12 · 2014: 1
- FWCI
- 8.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- UvA-DARE (University of Amsterdam) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- UvA-DARE (University of Amsterdam) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- Down syndrome, mTOR signaling, hippocampus, brain development, S6 kinase, S6 phosphorylation, eIF4E-binding protein 1, granulovacuolar degeneration, neurofibrillary tangles, Alzheimer disease pathology, pyramidal neurons, neurodegeneration
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Adolescent, Adult, Alzheimer Disease, Biotransformation, Child, Child, Preschool, Down Syndrome, Female, Hippocampus, Humans, Immunohistochemistry, Infant, Infant, Newborn, Male, Middle Aged, Neurons, Phosphorylation, Blotting, Western, Signal Transduction, Paraffin Embedding, Tissue Fixation, Ribosomal Protein S6 Kinases, Multiprotein Complexes, Young Adult, TOR Serine-Threonine Kinases
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