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

Prakash, P.; Jethava, K. P.; Korte, N.; Izquierdo, P.; Favuzzi, E.; Rose, I.; Guttenplan, K. A.; Dutta, S.; Rochet, C.; Fishell, G.; Liddelow, S.; Attwell, D.; Chopra, G.

doi:10.1101/2020.03.29.002857

bioRxiv · 10.1101/2020.03.29.002857

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

Prakash, P.·Jethava, K. P.·Korte, N.·Izquierdo, P.·Favuzzi, E.·Rose, I.·Guttenplan, K. A.·Dutta, S.·Rochet, C.·Fishell, G.·Liddelow, S.·Attwell, D.·Chopra, G.

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Abstract

Phagocytosis by glial cells is essential to regulate brain function during development and disease. Given recent interest in using amyloid {beta} (A{beta})-targeted antibodies as a therapy for patients with Alzheimers disease, removal of A{beta} by phagocytosis is likely protective early in Alzheimers disease, but remains poorly understood. Impaired phagocytic function of glial cells surrounding A{beta} plaques during later stages in Alzheimers disease likely contributes to worsened disease outcomes, 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 phagosomes 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. 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 removing A{beta} from the extracellular space, and thus could become a useful tool to study A{beta} clearance at different stages of Alzheimers disease.

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Prakash, P., Jethava, K. P., Korte, N., Izquierdo, P., Favuzzi, E., Rose, I., Guttenplan, K. A., Dutta, S., Rochet, C., Fishell, G., Liddelow, S., Attwell, D., Chopra, G.. 2020-03-29. Monitoring phagocytic uptake of amyloid β into glial cell lysosomes in real time. https://doi.org/10.1101/2020.03.29.002857

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