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

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Abstract

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 β (Aβ) or inhibitng enzymes that make it, and while removal of Aβ 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 Aβ1–42 analogue (AβpH) 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 AβpH in real time in live animals. We find that microglia phagocytose more AβpH than astrocytes in culture, in brain slices and in vivo. AβpH can be used to investigate the phagocytic mechanisms responsible for removing Aβ from the extracellular space, and thus could become a useful tool to study Aβ clearance at different stages of AD.

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

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Supplementary files

Article information


Submitted
27 Jun 2021
Accepted
07 Jul 2021
First published
21 Jul 2021

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2021, Advance Article
Article type
Edge Article

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

P. Prakash, K. P. Jethava, N. Korte, P. Izquierdo, E. Favuzzi, I. V. L. Rose, K. A. Guttenplan, P. Manchanda, S. Dutta, J. Rochet, G. Fishell, S. A. Liddelow, D. Attwell and G. Chopra, Chem. Sci., 2021, Advance Article , DOI: 10.1039/D1SC03486C

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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