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

Summary

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.

Graphical abstract

Highlights

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  A cellular model recapitulating neurogenesis defects was generated using AD iPSCs

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  LDN-193189 (LDN), isotretinoin, and SAG restored AD iPSCs neurogenesis

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  Morphological analysis revealed cell-type- and drug-type-dependent recovery effects

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  LDN induced neurogenesis through SMAD1/5/9-RUNX2 suppression and BMP4 hyposecretion

Abstract

Recent studies demonstrated the defects in neurogenesis in AD brains. Nakatsu et al. created a neuronal differentiation system in which sporadic and familial AD-derived iPSCs showed neurogenesis inhibition. They demonstrated that SMAD1/5/9 activation in AD iPSCs, which was induced by enhanced BMP4 secretion, inhibited neurogenesis and oligodendrogenesis via RUNX2 expression regulation while enhancing astrocyte differentiation.