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mTOR Hyperactivation in down syndrome hippocampus appears early during development.

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Dysregulated mammalian target of rapamycin (mTOR) signaling occurs in Down syndrome (DS) brain development, contributing to early abnormalities and later Alzheimer disease pathology. This pathway

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Area of Science:

  • Neuroscience
  • Developmental Biology
  • Cellular Aging

Background:

  • The mammalian target of rapamycin (mTOR) pathway regulates crucial cellular processes including aging and neurodegeneration.
  • Deregulation of mTOR signaling is implicated in various neurological disorders.
  • Down syndrome (DS) presents with early brain developmental issues and increased risk of Alzheimer disease (AD).

Purpose of the Study:

  • To investigate the role of mTOR pathway deregulation during early brain development in Down syndrome (DS).
  • To examine the expression patterns of mTOR signaling components in the developing and adult DS hippocampus.
  • To correlate mTOR pathway activation with Alzheimer disease-associated pathology in DS.

Main Methods:

  • Immunocytochemistry was used to analyze the expression and distribution of key mTOR signaling components.
  • Hippocampal tissues from prenatal and postnatal controls and DS subjects were examined.
  • Adult DS hippocampi with Alzheimer disease pathology were also analyzed.

Main Results:

  • Increased expression of phosphorylated mTOR, S6, S6 kinase, and 4E-BP1 was observed in the DS hippocampus compared to controls.
  • Specific mTOR components (phosphorylated S6 and S6 kinase) were detected prenatally and persisted postnatally in DS.
  • Elevated mTOR component expression correlated with neurofibrillary tangles and granulovacuolar degeneration in adult DS hippocampi.

Conclusions:

  • Dysregulated mTOR signaling contributes to early hippocampal developmental abnormalities in DS.
  • Persistent mTOR activation in DS may underlie hippocampal functional impairment preceding neurodegeneration.
  • mTOR pathway activation in the adult DS hippocampus is associated with Alzheimer disease-related histopathological changes.