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In Vitro Modeling of Down Syndrome Neurogenesis Using Human-Induced Pluripotent Stem Cells
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The mTOR Pathway: A Common Link Between Alzheimer's Disease and Down Syndrome

Abigail J Wohlfert1, Jeremiah Phares2, Ann-Charlotte Granholm2

  • 1Department of Modern Human Anatomy and Cell & Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

Journal of Clinical Medicine
|October 26, 2024
PubMed

Insights

Down syndrome (DS) and Alzheimer's disease (AD) share pathological pathways, particularly involving the mTOR pathway. Advanced omics technologies can illuminate these complex mechanisms in DS-AD.

Area of Science:

  • Neuroscience
  • Genetics
  • Cellular Biology

Background:

  • Down syndrome (DS) is a genetic condition associated with systemic dysregulation and increased risk of age-related diseases like Alzheimer's disease (AD).
  • The triplication of the Amyloid precursor protein (APP) gene and dysregulation of the mTOR pathway are implicated in DS-related AD (DS-AD) pathologies, including amyloid beta plaques (Aβ) and neurofibrillary tangles (NFT).
  • Existing research has not fully elucidated the specific mechanisms driving pathology progression in human DS-AD.

Purpose of the Study:

  • To investigate the under-explored molecular mechanisms underlying neurodegeneration in Down syndrome-related Alzheimer's disease (DS-AD).
  • To explore the role of the mTOR pathway and its regulators in the context of DS-AD.
  • To highlight the potential of novel omics technologies for uncovering unbiased insights into DS-AD pathogenesis.

Main Methods:

  • Review of existing literature on Down syndrome, Alzheimer's disease, and the mTOR pathway.
  • Discussion of recent advancements in omics platforms: genomics, spatial transcriptomics, proteomics, and metabolomics.
  • Proposal for the application of these omics methodologies to study DS-AD.

Main Results:

  • The mTOR pathway and its upstream regulators (insulin, PI3K/AKT, AMPK, amino acid signaling) are linked to key AD pathologies (Aβ, NFT).
  • A significant knowledge gap exists regarding the specific mechanisms of mTOR pathway involvement in human DS-AD.
  • Omics technologies offer unprecedented detail and an unbiased approach to dissect complex neurodegenerative pathways.

Conclusions:

  • Understanding the mTOR pathway's role in DS-AD is crucial for developing targeted therapeutic strategies.
  • The application of integrated omics approaches is essential for advancing our knowledge of DS-AD.
  • Further research utilizing advanced omics platforms is warranted to unravel the intricate cellular mechanisms of DS-AD.
Keywords:
intellectual disabilitymTORmetabolomicsneurodegenerationproteomicsspatial transcriptomics

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