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Krüppel-like factors KLF5 & KLF8 emerge as potential master transcriptional regulators of Alzheimer's disease, as revealed on cell fate regulomes in human brain organoids

  • A. Aubert
  • A.-C. Comby
  • A. Bramoulle
  • M.-G. Mendoza-Ferri
  • P. Azzolin
  • H. Li
  • A. Moussy
  • S. Das
  • B. M. Colombo
  • M. A. Mendoza-Parra1
  1. 1CNRS
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Abstract

In addition to the well described beta-amyloid plates accumulation and tau hyper-phosphorylation, Alzheimers disease (AD) is accompanied by major changes in gene expression. Herein, we aimed at revealing master transcription factors (TFs) responsible for gene expression changes during AD progression. For this, we have used human brain organoids (BORGs) harbouring AD-related genetic mutations (APP-Swedish, PSEN1-M146V), which were traced over multiple time-points by bulk and spatially-resolved transcriptomics. By reconstructing gene regulatory networks (GRNs) that recapitulate BORG development, we have identified a subset of 110 AD-specific master TFs, and for 75 of them we retrieved KLF5 and/or KLF8 binding motifs within their promoters. Furthermore, 64 of the AD-specific TFs found in BORGs are significantly over-expressed on AD human patients samples, confirming the relevance of these factors beyond the context of the familial genetic mutations. Finally, we have demonstrated that this AD-specific regulome is at least partially controlled by the aberrant CREB3L2-ATF4 heterodimer previously described as being induced by the beta-amyloid plates deposition. Overall, these findings reconstitute the regulome behind the progression of AD and highlights key TFs as potential druggable targets for the treatment of the disease.

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Cite

BibTeXRIS
BibTeX
@misc{aubert2026kruppellike,
  title = {{Krüppel-like factors KLF5 & KLF8 emerge as potential master transcriptional regulators of Alzheimer's disease, as revealed on cell fate regulomes in human brain organoids}},
  author = {A. Aubert and A.-C. Comby and A. Bramoulle and M.-G. Mendoza-Ferri and P. Azzolin and H. Li and A. Moussy and S. Das and B. M. Colombo and M. A. Mendoza-Parra},
  howpublished = {bioRxiv},
  year = {2026},
  month = jul,
  doi = {10.64898/2026.07.23.740401},
  url = {https://www.biorxiv.org/content/10.64898/2026.07.23.740401v2},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - Krüppel-like factors KLF5 & KLF8 emerge as potential master transcriptional regulators of Alzheimer's disease, as revealed on cell fate regulomes in human brain organoids
AU  - A. Aubert
AU  - A.-C. Comby
AU  - A. Bramoulle
AU  - M.-G. Mendoza-Ferri
AU  - P. Azzolin
AU  - H. Li
AU  - A. Moussy
AU  - S. Das
AU  - B. M. Colombo
AU  - M. A. Mendoza-Parra
PY  - 2026
DA  - 2026/07/23
PB  - bioRxiv
DO  - 10.64898/2026.07.23.740401
UR  - https://www.biorxiv.org/content/10.64898/2026.07.23.740401v2
AB  - In addition to the well described beta-amyloid plates accumulation and tau hyper-phosphorylation, Alzheimers disease (AD) is accompanied by major changes in gene expression. Herein, we aimed at revealing master transcription factors (TFs) responsible for gene expression changes during AD progression. For this, we have used human brain organoids (BORGs) harbouring AD-related genetic mutations (APP-Swedish, PSEN1-M146V), which were traced over multiple time-points by bulk and spatially-resolved transcriptomics. By reconstructing gene regulatory networks (GRNs) that recapitulate BORG development, we have identified a subset of 110 AD-specific master TFs, and for 75 of them we retrieved KLF5 and/or KLF8 binding motifs within their promoters. Furthermore, 64 of the AD-specific TFs found in BORGs are significantly over-expressed on AD human patients samples, confirming the relevance of these factors beyond the context of the familial genetic mutations. Finally, we have demonstrated that this AD-specific regulome is at least partially controlled by the aberrant CREB3L2-ATF4 heterodimer previously described as being induced by the beta-amyloid plates deposition. Overall, these findings reconstitute the regulome behind the progression of AD and highlights key TFs as potential druggable targets for the treatment of the disease.
ER  -