Rod-shaped microglia represent a morphologically distinct subpopulation of disease-associated microglia

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Microglia, the brain's immune cells, exhibit diverse states during pathology.
• Single-cell RNA sequencing reveals microglial heterogeneity, but links to morphology are unclear.
• Glutathione deficiency-induced oxidative stress models offer insights into neurodegeneration.

Purpose of the Study:

• To identify and characterize a distinct population of rod-shaped microglia in a model of oxidative stress.
• To investigate the molecular mechanisms and signaling pathways involved in the formation of rod-shaped microglia.
• To explore the potential role of rod-shaped microglia in early neurodegeneration.

Main Methods:

• Utilized glutamyl cysteine ligase (GCLC)-deficient mice to model glutathione deficiency and oxidative stress.
• Performed morphological and molecular analyses, including single-nucleus RNA sequencing.
• Investigated the role of C1q in rod-shaped microglia formation and analyzed gene expression profiles.

Main Results:

• Identified rod-shaped microglia with elongated morphology in GCLC-deficient mice during early neurodegeneration.
• Found that rod-shaped microglia formation is independent of C1q.
• Gene expression profiles of rod-shaped microglia resemble disease-associated microglia (DAM).
• Single-nucleus RNA sequencing suggested involvement of urokinase-type plasminogen activator (uPA) signaling and increased phosphorylated growth-associated protein 43 (GAP43).

Conclusions:

• Rod-shaped microglia represent a previously unrecognized activated population emerging early in neurodegeneration.
• Their formation appears to be regulated by a C1q-independent mechanism, potentially involving uPA signaling and GAP43.
• Understanding these early microglial responses may reveal novel therapeutic targets for neurodegenerative diseases.