A Common Haplotype Lowers PU.1 Expression in Myeloid Cells and Delays Onset of Alzheimer's Disease
Open accessPreprint — published as 10.1038/nn.4587 · Paper page
Abstract
A genome-wide survival analysis of 14,406 Alzheimer’s disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and fourteen novel loci associated with age at onset. LD score regression of 220 cell types implicated regulation of myeloid gene expression in AD risk. In particular, the minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability is enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affect the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells. Our results suggest that lower SPI1 expression reduces AD risk by regulating myeloid gene expression and cell function.
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Previous studies investigating the therapeutic potential of PU.1 for Alzheimer's disease have relied primarily on in vitro experiments using cell culture systems.
“Previous studies investigating the therapeutic potential of PU.1 for Alzheimer's disease have relied primarily on in vitro experiments using cell culture systems [22, 37, 38].”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [22]
The PU.1 functional experiments described in the Conditional and SMR analysis section used cultured BV2 mouse microglial cells, supporting the in vitro portion of the claim. But the paper also analyzes human Alzheimer’s disease genetic and age-at-onset data; it does not establish that previous research on PU.1’s therapeutic potential relied primarily on cell culture. The indexed passages provide section labels but no page numbers. (LLM, conf=0.84)
Experimental — accuracy not yet measuredKnockdown of PU.1 in BV-2 microglia stimulated with LPS reduces the expression of proinflammatory genes and immune response mediators, whereas overexpression of PU.1 has the opposite effect under the same conditions.
“On the one hand, the knockdown of PU.1 in BV‐2 microglia stimulated with LPS reduces the expression of proinflammatory genes and immune response mediators, whereas the overexpression of PU.1 has the opposite effect under the same conditions [22, 37].”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [22]
The functional-analysis discussion (page unavailable) reports that Spi1 knockdown in BV2 cells reduced expression of several inflammatory genes and that overexpression and knockdown produced often opposite gene-expression changes. The qPCR methods describe those BV2 experiments without LPS stimulation, so the source does not support the claim's LPS-stimulated condition. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn later stages of Alzheimer's disease, reducing PU.1 activity while increasing MEF2C activity inhibits harmful inflammation and supports neuroprotective microglial functions.
“in the later stages, it might be beneficial to reduce PU.1 activity while increasing MEF2C activity to inhibit harmful inflammation and support neuroprotective microglial functions”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [22]
The Conditional and SMR analysis section (page not supplied) reports that lowering Spi1/PU.1 reduced inflammatory markers in mouse microglial cells and suggests it may blunt pro-inflammatory responses. It also raises a possible neuroprotective role, but does not establish a benefit specifically in later-stage Alzheimer’s disease or support increasing MEF2C activity; a search for MEF2C found no relevant passage. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe single-nucleotide polymorphism rs1057233, located near the SPI1 gene, is associated with a reduced risk of developing Alzheimer's disease.
“A single‐nucleotide polymorphism (SNP) rs1057233, located near the SPI1 gene, is associated with a reduced risk of developing Alzheimer's disease.”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [22]
The protective effect of rs1057233 is associated with lower SPI1 expression in myeloid cells, such as monocytes and macrophages.
“This protective effect is associated with lower SPI1 expression in myeloid cells, such as monocytes and macrophages [22].”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [22]
The SPI1 gene, encoding the microglial transcription factor PU.1, was reported as a genetic risk factor for Alzheimer's disease.
“SPI1 gene, encoding the microglial transcription factor PU.1 was reported as a genetic risk factor for Alzheimer's disease [22].”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [22]
Low expression of PU.1 was suggested by a recent GWAS to be protective against AD.
“Importantly, low expression of PU.1 was suggested by a recent GWAS to be protective against AD 19 .”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [19]
Higher PU.1 expression in humans is likely to result in earlier AD onset.
“These results support previous reports demonstrating that higher PU.1 expression in humans is likely to result in earlier AD onset 19,48 .”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [19]
TYROBP is regulated by SPI1, a central hub for the network of genes involved in myeloid immune response in neurodegeneration.
“Also, TYROBP is regulated by SPI1, a central hub for the network of genes involved in myeloid immune response in neurodegeneration [93].”
From Sex-specific DNA methylation differences in Alzheimer’s disease pathology (2021) · cites this paper as [93]
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- Authors
- Huang, K.-L., Marcora, E., Pimenova, A. A., Di Narzo, A. F., Kapoor, M., Jin, S. C., Harari, O., Bertelsen, S., Fairfax, B. P., Czajkowski, J., Chouraki, V., Grenier-Boley, B., Bellenguez, C., Deming, Y., McKenzie, A., Raj, T., Renton, A. E., Budde, J., Smith, A., Fitzpatrick, A., Bis, J. C., DeStefano, A., Adams, H. H., Ikram, M. A., van der Lee, S., Del-Aguila, J. L., Fernandez, M. V., Ibañez, L., The International Genomics of Alzheimer’s Project, Initiative, T. A. D. N., Sims, R., Escott-Price, V., Mayeux, R., Haines, J. L., Farrer, L. A., Pericak-Vance, M. A., Lambert, J. C., van Duijn, C., Launer, L., Seshadri, S., Williams, J., Amouyel, P., Schellenberg, G. D., Zhang, B., Borecki, I., Kauwe, J. S. K., Cruchaga, C., Hao, K., & Goate, A. M.
- Affiliations
- Washington University in St. Louis (US)
- Icahn School of Medicine at Mount Sinai (US)
- Yale University (US)
- Centre for Human Genetics (GB)
- Boston University (US)
- Inserm (FR)
- University of Iceland (IS)
- University of Washington (US)
- Erasmus MC (NL)
- Cardiff University (GB)
- Columbia University (US)
- Case Western Reserve University (US)
- National Institutes of Health (US)
- University of Pennsylvania (US)
- Regeneron (United States) (US)
- Brigham Young University (US)
- Corresponding author
- Goate, Alison M
- ORCID
- Fairfax, Benjamin P
- Chouraki, Vincent
- Deming, Yuetiva
- Raj, Towfique
- Renton, Alan E
- Smith, Albert
- Bis, Joshua C
- DeStefano, Anita
- Adams, Hieab HH
- Ikram, M Arfan
- Sims, Rebecca
- Mayeux, Richard
- Haines, Jonathan L
- Farrer, Lindsay A
- Lambert, Jean Charles
- Launer, Lenore
- Seshadri, Sudha
- Amouyel, Philippe
- Schellenberg, Gerard D
- Borecki, Ingrid
- Cruchaga, Carlos
- Goate, Alison M
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2017-02-26
- OpenAlex
- W2595112338
- Cited by
- 6
- References
- 19
- Citations by year
- 2022: 1 · 2021: 2 · 2018: 2 · 2017: 1
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- Funders
- U.S. Department of Defense (U01 AG024904, W81XWH, W81XWH-12-2-, W81XWH-12, AG024904)
- Juvenile Diabetes Research Foundation International
- Alzheimer's Association (R01-AG044546, U01 AG032984, AG05681, U01 AG024904, AG033193, W81XWH-12-2-0012)
- Bristol-Myers Squibb (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Biogen (W81XWH-12-2-0012, U01 AG024904, AG024904)
- Alzheimer's Disease Neuroimaging Initiative (W81XWH-12-2–0012, U01 AG032984, U01AG024904, AG024904, W81XWH-12-2-)
- BioClinica (U01 AG024904, W81XWH-12-2-0012, AG024904)
- University of Texas Southwestern Medical Center
- Wellcome Trust
- Hope Center for Neurological Disorders
- Llywodraeth Cymru
- Alzheimer's Society
- National Institute for Health and Care Research (U01 AG024904)
- University of Cambridge
- Cardiff University
- National Natural Science Foundation of China (91643201, 2016YFC0206507, U01 AG024904, P01 AG026276, 21477087, W81XWH-12-2-0012)
- Bundesministerium für Bildung und Forschung
- Erasmus Medisch Centrum
- Alfried Krupp von Bohlen und Halbach-Stiftung
- University College London Hospitals NHS Foundation Trust
- Foundation for Biomedical Research and Innovation
- H. Lundbeck A/S (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Heinz Nixdorf Stiftung
- National Institutes of Health (W81XWH, W81XWH-12-2-0012)
- Gillings School of Public Health
- Medical Research Council (U01 AG024904)
- Menzies Centre for Australian Studies, King's College London, University of London
- Helmholtz Zentrum München
- National Institute on Aging (U01-AG-024904, AG03991, W81XWH-12-2–0012, AG 024904, RF1AG053303, AG 05681, R01AG035083, U01AG032984, AG033193, P 50 AG05681, R01AG044546, AG026276, AG032984, P01 AG0 3991, AG035083, AG049508, AG044546, U01AG049508, R01AG033193, P01AG026276)
- National Institute of Mental Health (U01 AG024904, W81XWH-12-2-0012)
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Neurological Disorders and Stroke (AG033193, R01-AG035083)
- National Institute of Child Health and Human Development
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, PU.1, CELF1, age of onset, myeloid cells, monocytes, macrophages, microglia, haplotypes, genetic susceptibility loci, transcription factor target genes, phagocytosis, heritability
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