Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Brain myeloid cells, including microglia and macrophages, are vital for brain development, homeostasis, and disease.
• Their diverse phenotypes, locations, and functions in various contexts remain incompletely understood.
• These cells are implicated in aging pathogenesis and neurodegenerative diseases.

Purpose of the Study:

• To systematically delineate brain macrophage populations using single-cell RNA sequencing (scRNA-seq) integration in mice.
• To resolve the ontogenetic origins and functional distinctions of myeloid cell populations in the brain.
• To identify potential cellular targets for treating neurodegenerative conditions.

Main Methods:

• Generation of a murine brain myeloid scRNA-seq dataset.
• Integration of scRNA-seq data to identify distinct cell populations.
• Analysis of ontogeny, phenotype, and function of brain myeloid cells in development, homeostasis, and disease models.

Main Results:

• The previously defined disease-associated microglia (DAM) population comprises two distinct lineages: TREM2-dependent DAM and monocyte-derived DIMs.
• TREM2-dependent DAM exhibit a neuroprotective signature.
• Monocyte-derived DIMs accumulate in the aging brain, suggesting a role in age-related inflammation.

Conclusions:

• Brain myeloid cell heterogeneity is more complex than previously thought, with distinct ontogenetic origins and functions.
• Disease-associated microglia (DAM) are not a single entity but comprise at least two separate cell types.
• These findings provide an ontogeny-resolved model of brain myeloid cells and identify potential therapeutic targets for neurodegeneration.