Cell type-specific histone acetylation landscape in Alzheimer’s disease reveals a putative role of MITF in microglia

Year: 2026

Type: preprint

Abstract: Alzheimer’s disease (AD) is characterised by aberrant amyloid beta and tau aggregation, neuroinflammation, demyelination and neurodegeneration, which have been linked to changes in cell-specific gene expression signatures. Among the mechanisms driving cell-type-specific transcriptional changes, histone acetylation plays a central role in regulating gene activity. While global alterations in histone acetylation have been implicated in AD, the contribution of individual cell types to these epigenetic changes remains poorly understood. To decode cell-type-specific changes in gene regulation in AD pathogenesis, we profiled histone H3 lysine 27 acetylation (H3K27ac) in microglia, oligodendrocytes and neurons from the prefrontal cortex of individuals with late-stage AD and non-dementia controls. Oligodendrocytes had the highest number of differential H3K27ac regions in AD, followed by microglia. Genes nearest to differential H3K27ac in purified microglia were enriched for phagocytosis, lipid processing, inflammatory and disease-associated cell state signature genes. Gene network analysis revealed downregulation of homeostatic genes in AD microglia and upregulation of immune activation, including signatures of lipid-handling and monocyte-derived macrophages. Oligodendrocyte co-regulated regions were indicative of increased MHC class I antigen presentation and altered neuron-oligodendrocyte interactions in AD. We identified H3K27ac allele-specific variants (ASVs) enriched near endolysosomal and ubiquitin-proteasome-associated genes in microglia and neurons. ASVs coincided with AD genome-wide association study (GWAS) risk loci, including CLU in oligodendrocytes and HLA-DRB1 in microglia. DNA motif analysis identified putative transcription factor drivers of AD glial dysregulation, including the lysosomal-associated MITF, Cap’n’collar (CNC) family (BACH1 and NFE2) and AP-1 activation in microglia. DNA binding of the MITF protein in human microglia was localised to lysosomal-associated genes and enriched in H3K27ac regions upregulated in AD and near disease-associated microglia (DAM) genes. Collectively, these findings implicate lysosomal dysfunction and upstream transcriptional regulation via MITF as key processes in AD microglia.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.09.09.750356

Authors: Charbel Gergian, Paulina Urbanaviciute, Philippa M. Wells, Janis L. Transfeld, Aydan Askarova, Reuben M. Yaa, Yukyee Wu, Kevin Chris Ziegler, Christian K. Nickl, Martina P. Pasillas, Johannes C. M. Schlachetzki, Inge R. Holtman, Peter T. Nelson, Robert A. Rissman, James B. Brewer, Sarah J. Marzi, Christopher K. Glass, Alexi Nott

Institutions: UK Dementia Research Institute, Imperial College London, King's College London, University of California San Diego, University Medical Center Groningen, University of Groningen, University of Kentucky, University of Southern California

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Cellular and Molecular Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: Alzheimer's Association, BrightFocus Foundation, Arizona Department of Health Services, Cure Alzheimer's Fund, National Institute for Health and Care Research, Imperial College London, University College London, UK Dementia Research Institute, Arizona Biomedical Research Commission, National Institutes of Health, University of California, San Diego, Medical Research Council, NIHR Imperial Biomedical Research Centre, National Institute on Aging, National Institute of Neurological Disorders and Stroke

OpenAlex ID: W7212712770