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Basic Science and Pathogenesis.

Holly N Cukier1,2, Yeunjoo E Song3, Lauren E Coombs2

  • 1Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.

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Summary
This summary is machine-generated.

Mosaic loss of the Y chromosome (LOY) is linked to Alzheimer's disease (AD) risk. Researchers created paired stem cell lines from individuals with and without LOY to study its impact on AD. This research aids in understanding LOY's role in AD pathogenesis.

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Area of Science:

  • Genetics
  • Neuroscience
  • Cell Biology

Background:

  • Mosaic loss of the Y chromosome (LOY) is an age-related phenomenon in males.
  • LOY is associated with an increased risk of Alzheimer's disease (AD).
  • LOY may serve as a marker for genomic instability preceding AD phenotypes.

Purpose of the Study:

  • To investigate the mechanism by which LOY contributes to AD risk.
  • To generate isogenic cell lines for studying LOY's impact on AD-relevant cell types.

Main Methods:

  • Screened 1,068 males for LOY using genotyping data.
  • Reprogrammed peripheral blood mononuclear cells (PBMCs) into induced pluripotent stem cells (iPSCs).
  • Generated isogenic iPSC pairs (LOY present vs. absent) from affected and normal individuals.

Main Results:

  • Identified 41 males (3.83%) with detectable LOY, correlating with age.
  • Successfully created isogenic iPSC lines from three individuals (2 cognitively normal, 1 with AD).
  • Confirmed LOY status via CNV TaqMan assays or whole genome sequencing.

Conclusions:

  • Generated paired iPSC lines from AD and cognitively normal individuals with and without LOY.
  • These isogenic cell lines enable direct examination of LOY's effect on AD-relevant cell types.
  • Provides a novel cellular model for dissecting the biological link between LOY and AD.