Monitoring phagocytic uptake of amyloid β into glial cell lysosomes in real time

Phagocytosis by glial cells is essential to regulate brain function during health and disease. Therapies for Alzheimer's disease (AD) have primarily focused on targeting antibodies to amyloid beta (A beta) or inhibitng enzymes that make it, and while removal of A beta by phagocytosis is protective early in AD it remains poorly understood. Impaired phagocytic function of glial cells during later stages of AD likely contributes to worsened disease outcome, but the underlying mechanisms of how this occurs remain unknown. We have developed a human A beta(1-42) analogue (A beta(pH)) that exhibits green fluorescence upon internalization into the acidic organelles of cells but is non-fluorescent at physiological pH. This allowed us to image, for the first time, glial uptake of A beta(pH) in real time in live animals. We find that microglia phagocytose more A beta(pH) than astrocytes in culture, in brain slices and in vivo. A beta(pH) can be used to investigate the phagocytic mechanisms responsible for removing A beta from the extracellular space, and thus could become a useful tool to study A beta clearance at different stages of AD.

Automated summary

Phagocytosis by glial cells plays a crucial role in regulating brain function, especially in the pathogenesis and progression of Alzheimer's disease. The newly developed Aβ(pH) analogue provides a tool to study the mechanisms of glial cell clearance of Aβ, offering potential insights into Aβ clearance at different stages of AD.