Overactive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer's Disease

J Alzheimers Dis. 2018;62(1):175-202. doi: 10.3233/JAD-170830.


The BRCA1 protein, one of the major players responsible for DNA damage response has recently been linked to Alzheimer's disease (AD). Using primary fibroblasts and neurons reprogrammed from induced pluripotent stem cells (iPSC) derived from familial AD (FAD) patients, we studied the role of the BRCA1 protein underlying molecular neurodegeneration. By whole-transcriptome approach, we have found wide range of disturbances in cell cycle and DNA damage response in FAD fibroblasts. This was manifested by significantly increased content of BRCA1 phosphorylated on Ser1524 and abnormal ubiquitination and subcellular distribution of presenilin 1 (PS1). Accordingly, the iPSC-derived FAD neurons showed increased content of BRCA1(Ser1524) colocalized with degraded PS1, accompanied by an enhanced immunostaining pattern of amyloid-β. Finally, overactivation of BRCA1 was followed by an increased content of Cdc25C phosphorylated on Ser216, likely triggering cell cycle re-entry in FAD neurons. This study suggests that overactivated BRCA1 could both influence PS1 turnover leading to amyloid-β pathology and promote cell cycle re-entry-driven cell death of postmitotic neurons in AD.

Keywords: Alzheimer’s disease; BRCA1; DNA damage response; cell cycle re-entry; presenilin 1; ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism
  • BRCA1 Protein / metabolism*
  • Cells, Cultured
  • Cellular Reprogramming Techniques
  • Computational Biology
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gene Expression
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / pathology
  • Neurons / metabolism*
  • Neurons / pathology
  • Phosphorylation
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism*
  • Presenilin-2 / genetics
  • Presenilin-2 / metabolism
  • Signal Transduction
  • Transcriptome
  • cdc25 Phosphatases / metabolism


  • Amyloid beta-Peptides
  • BRCA1 Protein
  • BRCA1 protein, human
  • PSEN1 protein, human
  • PSEN2 protein, human
  • Presenilin-1
  • Presenilin-2
  • CDC25C protein, human
  • cdc25 Phosphatases