Work

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

Year: 2026

Type: preprint

Abstract: SUMMARY In addition to the well described beta-amyloid plaques accumulation and tau hyper- phosphorylation, Alzheimer’s 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) and applying a machine learning framework that classifies transcription factors (TFs) based on predicted regulatory cascade dynamics, we identified a core set of 64 AD specific master TFs. These factors were subsequently validated by their over expression in transcriptomes from human patients. Strikingly, both KLF5 and KLF8 showed promoter enrichment across more than half of the AD specific transcription factors, strongly suggesting that they occupy key regulatory positions within the AD regulome. This functional relevance was further emphasized by spatially resolved transcriptomics, which demonstrated that their regional over expression mirrors the spatial distribution of AD markers in human patient samples. Finally, we have demonstrated that this AD-specific regulome is controlled by the aberrant CREB3L2-ATF4 heterodimer previously described as being induced by the beta-amyloid plaques 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.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.07.23.740401