PU.1 regulates Alzheimer’s disease-associated genes in primary human microglia
Open accessAbstract
BACKGROUND: Microglia play critical roles in the brain during homeostasis and pathological conditions. Understanding the molecular events underpinning microglial functions and activation states will further enable us to target these cells for the treatment of neurological disorders. The transcription factor PU.1 is critical in the development of myeloid cells and a major regulator of microglial gene expression. In the brain, PU.1 is specifically expressed in microglia and recent evidence from genome-wide association studies suggests that reductions in PU.1 contribute to a delayed onset of Alzheimer's disease (AD), possibly through limiting neuroinflammatory responses. METHODS: To investigate how PU.1 contributes to immune activation in human microglia, microarray analysis was performed on primary human mixed glial cultures subjected to siRNA-mediated knockdown of PU.1. Microarray hits were confirmed by qRT-PCR and immunocytochemistry in both mixed glial cultures and isolated microglia following PU.1 knockdown. To identify attenuators of PU.1 expression in microglia, high throughput drug screening was undertaken using a compound library containing FDA-approved drugs. NanoString and immunohistochemistry was utilised to investigate the expression of PU.1 itself and PU.1-regulated mediators in primary human brain tissue derived from neurologically normal and clinically and pathologically confirmed cases of AD. RESULTS: Bioinformatic analysis of gene expression upon PU.1 silencing in mixed glial cultures revealed a network of modified AD-associated microglial genes involved in the innate and adaptive immune systems, particularly those involved in antigen presentation and phagocytosis. These gene changes were confirmed using isolated microglial cultures. Utilising high throughput screening of FDA-approved compounds in mixed glial cultures we identified the histone deacetylase inhibitor vorinostat as an effective attenuator of PU.1 expression in human microglia. Further characterisation of vorinostat in isolated microglial cultures revealed gene and protein changes partially recapitulating those seen following siRNA-mediated PU.1 knockdown. Lastly, we demonstrate that several of these PU.1-regulated genes are expressed by microglia in the human AD brain in situ. CONCLUSIONS: Collectively, these results suggest that attenuating PU.1 may be a valid therapeutic approach to limit microglial-mediated inflammatory responses in AD and demonstrate utility of vorinostat for this purpose.
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PU.1 reduction has been reported to result in the down-regulation of massive proinflammatory genes and cell cycle-related genes.
“given that PU.1 reduction has been reported to result in the down-regulation of massive proinflammatory genes and cell cycle–related genes (14, 43).”
From Arresting the bad seed: HDAC3 regulates proliferation of different microglia after ischemic stroke (2024) · cites this paper as [43]
The Results section on microarray analysis reports 129 downregulated genes after PU.1 silencing in mixed glial cultures. But the Results section on isolated human microglia says inflammatory cytokines and chemokines were largely unaltered, and the copy does not establish downregulation of cell cycle-related genes. The cited paper therefore supports broad gene downregulation, not the specific gene categories claimed. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAnother similar study observed no reduction in microglia number, though PU.1 loss was measured at culture level so reduction could not be quantified on single-cell level.
“Another similar study observed no reduction in microglia number, though PU.1 loss was measured at a culture level so the reduction could not be quantified on a single-cell level31.”
From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [31]
The Results section, “Confirmation of microarray analysis in isolated human brain microglia” (page unavailable), reports no change in cell number or microglial purity after PU.1 knockdown and an approximately 60% reduction in PU.1 protein expression. It does not state that the reduction could not be quantified at the single-cell level; the Methods section describes imaging-based measurement of staining intensity and scoring of individual cells. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIncreased PU.1 expression levels are associated with Alzheimer's disease and Huntington's disease.
“Increased PU.1 expression levels are associated with AD (Gjoneska et al., 2015; Huang et al., 2017; Rustenhoven et al., 2018) and Huntington’s disease (Crotti et al., 2014)”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Rustenhoven et al., 2018
High-throughput screening of 1280 FDA-approved compounds identified vorinostat as a candidate drug for attenuating PU.1 level, which mimics partial effects of PU.1 knockdown.
“High-throughput screening of 1280 US Food and Drug Administration–approved compounds also identified an HDAC inhibitor, vorinostat, as a candidate drug for attenuating PU.1 level, which is then found to mimic partial effects of PU.1 knockdown (43).”
From Arresting the bad seed: HDAC3 regulates proliferation of different microglia after ischemic stroke (2024) · cites this paper as [43]
In BV2 microglial cells, protective low expression of PU.1 led to decreased phagocytic uptake.
“In BV2 microglial cells protective low expression of PU.1 led to decreased phagocytic uptake (Fig. 2), which is in line with previous data showing that siRNA knock-down of PU.1 in human microglia in vitro reduces expression of genes involved in phagocytic and antigen presentation pathways (Rustenhoven et al., 2018).”
From Alzheimer's-associated PU.1 expression levels regulate microglial inflammatory response (2021) · cites this paper as Rustenhoven et al., 2018
Analysis of mixed microglia/pericyte cultures where PU.1 was reduced via siRNA showed reduced expression of DAP12 and HLA-DR/DP/DQ.
“Analysis of mixed microglia/pericyte cultures where PU.1 was reduced via siRNA showed reduced expression of DAP12 and HLA-DR/DP/DQ31.”
From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [31]
Previous work has identified that Spi1 is able to influence multiple gene networks in microglia and has been proposed as central to a network of AD risk genes conserved between species.
“Previous work has identified that Spi1 is able to influence multiple gene networks in microglia5,7,31 and has been proposed as central to a network of AD risk genes that are conserved between species50.”
From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [31]
In vitro cell culture studies have demonstrated that Spi1 regulates the expression of AD-associated genes involved in the phagocytic activity and immune response of microglia.
“In vitro cell culture studies have demonstrated that Spi1 regulates the expression of AD-associated genes involved in the phagocytic activity and immune response of microglia1,6.”
From Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aβ amyloidosis (2024) · cites this paper as [6]
HLA-DPA1 encodes microglia receptors involved in antigen presentation and is regulated by PU.1.
“which encodes microglia receptors involved in antigen presentation and is regulated by PU.1 [61].”
From Sex-specific DNA methylation differences in Alzheimer’s disease pathology (2021) · cites this paper as [61]
In males, the most significant CpG-gene expression was for HLA-DRB1, another PU.1 target gene.
“In males, the most significant CpG-gene expression was for HLA-DRB1, another PU.1 target gene [61].”
From Sex-specific DNA methylation differences in Alzheimer’s disease pathology (2021) · cites this paper as [61]
PU.1 regulates expression of genes associated with AD risk or onset, including ABCA7, CD33, TREM2, MS4A4A, MS4A6A, TYROBP, Aif1, and MYBPC3.
“In addition, PU.1 can regulate expression of genes associated with AD risk or onset, including ABCA7, CD33, TREM2, MS4A4A, MS4A6A, TYROBP, Aif1, and MYBPC3 [492, 493].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [493]
Rustenhoven et al. identified vorinostat as an effective attenuator of PU.1 in primary human microglia-enriched culture.
“Furthermore, Rustenhoven et al. identified another HDAC class I/II/IV inhibitor vorinostat as an effective attenuator of PU.1 in primary human microglia-enriched culture [30, 39].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [30]
Silencing PU.1 in human microglia culture suppressed expression of DAP12/TYROBP, TREM2, LST1, CD11b, MRC1, CEBPA, PTPRC, and MHC class II genes HLA-DR, HLA-DP, and HLA-DQ.
“Silencing of PU.1 in human microglia culture suppressed expression of myeloid adapter protein DAP12/TYROBP, TREM2, LST1, CD11b, MRC1, CEBPA, PTPRC and MHC class II genes HLA-DR, HLA-DP and HLA-DQ [30, 31], suggesting its role in antigen presentation and pro-inflammatory response by PU.1 [30, 31].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [30]
Vorinostat treatment reduced DAP12 expression, whereas CD45 and HLA-DR, HLA-DP, or HLA-D1 expression remained unchanged.
“However, vorinostat treatment showed reduction in DAP12 expression, whereas expression of CD45 and HLA-DR, HLA-DP or HLA-D1 remained unchanged [30].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [30]
PU.1 has a role in antigen presentation and pro-inflammatory response.
“suggesting its role in antigen presentation and pro-inflammatory response by PU.1 [30, 31].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [30]
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- Authors
- Rustenhoven, J., Smith, A. M., Smyth, L. C., Jansson, D., Scotter, E. L., Swanson, M. E. V., Aalderink, M., Coppieters, N., Narayan, P., Handley, R., Overall, C., Park, T. I. H., Schweder, P., Heppner, P., Curtis, M. A., Faull, R. L. M., & Dragunow, M.
- Affiliations
- University of Auckland (NZ)
- Imperial College London (GB)
- Auckland City Hospital (NZ)
- Corresponding author
- Dragunow, Mike
- ORCID
- Venue
- Molecular Neurodegeneration
- Published
- 2018-08-20
- Volume
- 13
- Issue
- 1
- Pages
- 44-44
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC6102813
- OpenAlex
- W2888188888
- Cited by
- 155
- References
- 83
- Citations by year
- 2026: 8 · 2025: 26 · 2024: 20 · 2023: 21 · 2022: 31 · 2021: 22 · 2020: 17 · 2019: 9 · 2018: 1
- FWCI
- 5.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- ResearchSpace (University of Auckland) (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- Hugh Green Foundation
- Neurological Foundation of New Zealand
- Health Research Council of New Zealand
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- PU.1, Alzheimer's disease, microglia, transcription factors, neuroinflammation, vorinostat, histone deacetylase inhibitors, microglial gene expression, antigen presentation, phagocytosis, mixed glial cultures, therapeutic target
- MeSH terms
- Vorinostat, Proto-Oncogene Protein Spi-1, Alzheimer Disease, Gene Expression Regulation, Humans, Proto-Oncogene Proteins, Trans-Activators, Microglia, Histone Deacetylase Inhibitors
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