Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia
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1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.;
2. Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan.;
3. 10x Genomics, Pleasanton, CA, USA.;
4. Deepcell, Menlo Park, CA, USA.;
5. Department of Clinical Laboratory and Internal Medicine, National Center of Neurology and Psychiatry (NCNP), National Center Hospital, Tokyo, Japan.;
6. Department of Brain Bank, Mihara Memorial Hospital, Isesaki, Japan.;
7. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Nature Immunology
2023
10.1038/s41590-022-01403-y
English
Zhou Y, Tada M, Cai Z, Andhey PS, Swain A, Miller KR, Gilfillan S, Artyomov MN, Takao M, Kakita A, Colonna M. Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia. Nat Immunol. 2023 Jan 19. doi: 10.1038/s41590-022-01403-y. Epub ahead of print. PMID: 36658241.. Share Research.
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.
dysregulated microglia
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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