BMP4-SMAD1/5/9-RUNX2 pathway activation inhibits neurogenesis and oligodendrogenesis in Alzheimer's patients' iPSCs in senescence-related conditions

Stem Cell Reports. 2023 Mar 14;18(3):688-705. doi: 10.1016/j.stemcr.2023.01.004. Epub 2023 Feb 9.


In addition to increasing β-amyloid plaque deposition and tau tangle formation, inhibition of neurogenesis has recently been observed in Alzheimer's disease (AD). This study generated a cellular model that recapitulated neurogenesis defects observed in patients with AD, using induced pluripotent stem cell lines derived from sporadic and familial AD (AD iPSCs). AD iPSCs exhibited impaired neuron and oligodendrocyte generation when expression of several senescence markers was induced. Compound screening using these cellular models identified three drugs able to restore neurogenesis, and extensive morphological quantification revealed cell-line- and drug-type-dependent neuronal generation. We also found involvement of elevated Sma- and Mad-related protein 1/5/9 (SMAD1/5/9) phosphorylation and greater Runt-related transcription factor 2 (RUNX2) expression in neurogenesis defects in AD. Moreover, BMP4 was elevated in AD iPSC medium during neural differentiation and cerebrospinal fluid of patients with AD, suggesting a BMP4-SMAD1/5/9-RUNX2 signaling pathway contribution to neurogenesis defects in AD under senescence-related conditions.

Keywords: Alzheimer’s disease; BMP4; RUNX2; SMAD1/5/9; compound screening; induced pluripotent stem cell (iPSC); morphological analysis; neurogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / metabolism
  • Amyloid beta-Peptides / metabolism
  • Bone Morphogenetic Protein 4 / metabolism
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Humans
  • Induced Pluripotent Stem Cells* / metabolism
  • Neurogenesis / physiology
  • Neurons / metabolism
  • Smad Proteins


  • Amyloid beta-Peptides
  • BMP4 protein, human
  • Bone Morphogenetic Protein 4
  • Core Binding Factor Alpha 1 Subunit
  • RUNX2 protein, human
  • Smad Proteins