mTOR Hyperactivation in down syndrome hippocampus appears early during development

Topic: Brain proteins, microglia and lab models

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 hippocampal functional impairment developing before neurodegeneration. Moreover, the expression patterns of mTOR components in adult DS hippocampus support its association with Alzheimer disease-related histopathologic changes.

Key findings

• 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.
• These findings suggest that a dysregulated mTOR pathway may contribute to both early hippocampal developmental abnormalities and hippocampal functional impairment developing before neurodegeneration.

Why it matters

In developing hippocampi from people with Down syndrome, components of the mTOR signaling pathway were increased compared with controls and persisted after birth. This is a post-mortem tissue study suggesting dysregulated mTOR may contribute to early developmental abnormalities, not a treatment trial.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1097/nen.0000000000000083
• PubMed: 24918639
• Original source →

May need a subscription OpenAlex found no free copy of the full text (checked 6 Feb 1020), so the publisher may charge for it. The PubMed abstract is free.

@article{iyer2014-24918639,
  author  = {Iyer, A. M. and van Scheppingen, J. and Milenkovic, I. and Anink, J. J. and Adle-Biassette, H. and Kovacs, G. G. and Aronica, E.},
  title   = {{mTOR Hyperactivation in down syndrome hippocampus appears early during development}},
  journal = {Journal of neuropathology and experimental neurology},
  year    = {2014},
  doi     = {10.1097/nen.0000000000000083},
  pmid    = {24918639},
  url     = {https://doi.org/10.1097/nen.0000000000000083}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry Acta neuropathologica · 2006-08-12 · usefulness score 60/100 · Brain tissue and pathology
• The pathological association between Down syndrome and Alzheimer disease Mechanisms of ageing and development · 1988-05-01 · usefulness score 44/100 · Down syndrome and Alzheimer's
• Neurofibrillary tangles, granulovacuolar degeneration, and neuron loss in Down Syndrome: quantitative comparison with Alzheimer dementia Annals of neurology · 1980-05-01 · usefulness score 43/100 · Down syndrome and Alzheimer's
• Communication breaks-Down: from neurodevelopment defects to cognitive disabilities in Down syndrome Progress in neurobiology · 2010-01-25 · usefulness score 40/100 · Down syndrome and Alzheimer's
• Neuropathology of Down syndrome and Alzheimer disease American journal of medical genetics. Supplement · 1990-01-01 · usefulness score 36/100 · Down syndrome and Alzheimer's

Later studies that cite this one

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• mTOR in Down syndrome: Role in Aß and tau neuropathology and transition to Alzheimer disease-like dementia Free radical biology & medicine · 2017-08-12 · usefulness score 45/100 · Down syndrome and Alzheimer's
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• Signalling Pathways Implicated in Alzheimer's Disease Neurodegeneration in Individuals with and without Down Syndrome International journal of molecular sciences · 2020-09-20 · usefulness score 38/100 · Down syndrome and Alzheimer's
• Mitochondrial Imbalance in Down Syndrome: A Driver of Accelerated Brain Aging? Aging and disease · 2025-04-06 · usefulness score 36/100 · Down syndrome and Alzheimer's

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