DAP12-deficient microglia adopt a TREM2-independent antigen-presenting state with a glial-to-neuronal cascade in Nasu-Hakola disease
- 1RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco
Abstract
Nasu-Hakola disease (NHD), a dementia with about 200 cases worldwide, is caused by loss-of-function mutation of TYROBP, encoding DAP12, or its receptor TREM2. TREM2-DAP12 is the switch that converts microglia from a surveillant to a reactive state; what DAP12-deficient microglia become and to what extent they reshape their microenvironment is unknown. We profiled prefrontal cortex and hippocampus from an NHD donor and control by single-nucleus RNA sequencing and mapped the glial changes in situ by spatial transcriptomics. NHD microglia adopted a CIITA-driven, MHC class II-high antigen-presenting state with complement, iron and glycolytic programs and Fc receptors but not the TREM2-dependent lipid program. Astrocytes became pan-reactive and lost metallothionein expression, oligodendrocytes lost mature cells and cholesterol synthesis, and excitatory neurons lost presynaptic and activity programs, consistently between regions and across a published cohort. DAP12 deficiency left microglia in an antigen-presenting state short of the TREM2-dependent arm, accompanied by a glial-to-neuronal cascade.
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BibTeX
@misc{leon2026dap12deficient,
title = {{DAP12-deficient microglia adopt a TREM2-independent antigen-presenting state with a glial-to-neuronal cascade in Nasu-Hakola disease}},
author = {J. Leon and S. Yoshinaga and I. Koya and G. Palafox and Y. Ando and K.-i. Kubo and J. Moody and M. Takao and P. Carninci and J. Shin and C. Condello and H. Okano and C. C. Hon and S. Morimoto},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.07.757387},
url = {https://www.biorxiv.org/content/10.64898/2026.10.07.757387v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - DAP12-deficient microglia adopt a TREM2-independent antigen-presenting state with a glial-to-neuronal cascade in Nasu-Hakola disease
AU - J. Leon
AU - S. Yoshinaga
AU - I. Koya
AU - G. Palafox
AU - Y. Ando
AU - K.-i. Kubo
AU - J. Moody
AU - M. Takao
AU - P. Carninci
AU - J. Shin
AU - C. Condello
AU - H. Okano
AU - C. C. Hon
AU - S. Morimoto
PY - 2026
DA - 2026/10/07
PB - bioRxiv
DO - 10.64898/2026.10.07.757387
UR - https://www.biorxiv.org/content/10.64898/2026.10.07.757387v1
AB - Nasu-Hakola disease (NHD), a dementia with about 200 cases worldwide, is caused by loss-of-function mutation of TYROBP, encoding DAP12, or its receptor TREM2. TREM2-DAP12 is the switch that converts microglia from a surveillant to a reactive state; what DAP12-deficient microglia become and to what extent they reshape their microenvironment is unknown. We profiled prefrontal cortex and hippocampus from an NHD donor and control by single-nucleus RNA sequencing and mapped the glial changes in situ by spatial transcriptomics. NHD microglia adopted a CIITA-driven, MHC class II-high antigen-presenting state with complement, iron and glycolytic programs and Fc receptors but not the TREM2-dependent lipid program. Astrocytes became pan-reactive and lost metallothionein expression, oligodendrocytes lost mature cells and cholesterol synthesis, and excitatory neurons lost presynaptic and activity programs, consistently between regions and across a published cohort. DAP12 deficiency left microglia in an antigen-presenting state short of the TREM2-dependent arm, accompanied by a glial-to-neuronal cascade.
ER -