ArticleNature immunology2023
Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia.
Article in Nature immunology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 37 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
37 citing papers in PubMed, 49 citations in OpenAlex.
- Article
- Article
- CSF1R-related leukoencephalopathy: experimental models and potential for treatment.Disease models & mechanisms · 2026Review
- Microglial ITAM & ITIM Signaling in Neurodegenerative Disease and Brain Aging.Journal of molecular biology · 2026Review
- Brain-engrafted monocyte-derived macrophages from blood and skull-bone marrow exhibit distinct properties.Neuron · 2026Article
- The impact of Trem2-mediated macrophage polarization on the mechanisms of allergic rhinitis.Scientific reports · 2026Article
- The role of DAP12 in immune-related inflammatory diseases.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Review
- Axonopathy: mechanisms and potential therapeutic targets for neurodegenerative diseases.Translational neurodegeneration · 2026Review
- Decoding TREM2 Signaling Pathways: Linking Macrophage Glycolysis to Inflammatory Diseases in the CNS.Neurology(R) neuroimmunology & neuroinflammation · 2026Review
- Parkinson's disease: spatiotemporal regulation and therapeutic prospects of TREM2-mediated microglial responses.NPJ Parkinson's disease · 2026Review
- TREM2 in age-related macular degeneration: a microglia-centered perspective in the retinal myeloid landscape.Frontiers in ophthalmology · 2026Review
- The Dual Role of RUNX1 in Inflammation-Driven Age-Related Diseases: From Molecular Mechanisms to Clinical Translation.Biomedicines · 2025Review
- Decoding the Therapeutic Effects of Acupuncture in Hemorrhagic Stroke Using Single-Cell RNA Sequencing.CNS neuroscience & therapeutics · 2025Article
- A scoping review of stem cell models of leukodystrophies: advances in understanding pathophysiological mechanisms.NPJ genomic medicine · 2025Article
- Is TREM2 a Stretch: Implications of TREM2 Along Spinal Cord Circuits in Health, Aging, Injury, and Disease.Cells · 2025Review
- TREM2 and LAG-3 in cancer and Alzheimer's disease immunotherapy.Trends in pharmacological sciences · 2025Review
- Review
- Microglia loss triggers glial stress and white matter damage in human leukodystrophy.Nature immunology · 2025Article
- Mutations in the human CSF1R gene impact microglia's maintenance of brain white matter integrity.Nature immunology · 2025Article
- Targeting TYROBP to influence the immune microenvironment and osteogenic differentiation of mesenchymal stem cells.Journal of orthopaedic surgery and research · 2025Article
Corrections and comments
- Commented on by
- Erratum issued
Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
Abstract
The TREM2-DAP12 receptor complex sustains microglia functions. Heterozygous hypofunctional TREM2 variants impair microglia, accelerating late-onset Alzheimer's disease. Homozygous inactivating variants of TREM2 or TYROBP-encoding DAP12 cause Nasu-Hakola disease (NHD), an early-onset dementia characterized by cerebral atrophy, myelin loss and gliosis. Mechanisms underpinning NHD are unknown. Here, single-nucleus RNA-sequencing analysis of brain specimens from DAP12-deficient NHD individuals revealed a unique microglia signature indicating heightened RUNX1, STAT3 and transforming growth factor-β signaling pathways that mediate repair responses to injuries. This profile correlated with a wound healing signature in astrocytes and impaired myelination in oligodendrocytes, while pericyte profiles indicated vascular abnormalities. Conversely, single-nuclei signatures in mice lacking DAP12 signaling reflected very mild microglial defects that did not recapitulate NHD. We envision that DAP12 signaling in microglia attenuates wound healing pathways that, if left unchecked, interfere with microglial physiological functions, causing pathology in human. The identification of a dysregulated NHD microglia signature sparks potential therapeutic strategies aimed at resetting microglia signaling pathways.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.