# Endogenous γ-Secretase Is Linked to Phagocytic Activity in Microglial Cells

## TL;DR

This study shows that γ-secretase activity in microglial cells is linked to their ability to phagocytose particles, suggesting a key role for this enzyme in microglial function.

## Contribution

The study confirms a direct link between endogenous γ-secretase activity and phagocytic activity in microglial cells using a novel FRET-based biosensor.

## Key findings

- BV-2 microglial cells show cell-to-cell variation in endogenous γ-secretase activity.
- Lower γ-secretase activity correlates with impaired phagocytosis of E. coli bioparticles.
- Reduced phagocytic activity is associated with decreased γ-secretase activity in Zymosan bioparticle experiments.

## Abstract

γ-Secretase has primarily been studied in neurons, whereas increasing evidence highlights its importance in microglia. Previous research has shown that the pharmacological inhibition of γ-secretase impairs microglial phagocytic activity. In this study, we used a genetically encoded Förster resonance energy transfer (FRET)-based biosensor to record γ-secretase activity, aiming to determine if naturally occurring cell-by-cell variations in endogenous γ-secretase activity are associated with phagocytic activity. Using the Notch1 N100 Y-T biosensor, we found that the regulation of endogenous γ-secretase activity varies among individual BV-2 microglial cells. Our multiplexed time-lapse imaging revealed that the phagocytosis of E. coli bioparticles was impaired in cells with lower γ-secretase activity compared to those with higher activity. Complementary biochemical analysis, utilizing Zymosan bioparticles and fluorescence-activated cell sorting (FACS), further demonstrated that cells with reduced phagocytic activity exhibited decreased endogenous γ-secretase activity. Collectively, our confirmatory study supports previous findings that microglial phagocytic activity is closely linked to γ-secretase and emphasizes the essential role of γ-secretase in microglia.