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

Priya Prakash; Krupal P. Jethava; Nils Korte; Pablo Izquierdo; Emilia Favuzzi; Indigo V. L. Rose; Kevin A. Guttenplan; Palak Manchanda; Sayan Dutta; Jean-Christophe Rochet; Gord Fishell; Shane A. Liddelow; David Attwell; Gaurav Chopra

doi:10.1039/D1SC03486C

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

Priya Prakash,

‡^a Krupal P. Jethava,

‡^a Nils Korte,

‡^b Pablo Izquierdo,

‡^b Emilia Favuzzi,^cd Indigo V. L. Rose,

^e Kevin A. Guttenplan,

^f Palak Manchanda,

^a Sayan Dutta,^g Jean-Christophe Rochet,

^gh Gord Fishell,^cd Shane A. Liddelow,

^eij David Attwell

^b and Gaurav Chopra

*^ahklm

Author affiliations

* Corresponding authors

^a Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
E-mail: gchopra@purdue.edu

^b Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK

^c Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA

^d Stanley Center at the Broad, 75 Ames Street, Cambridge, MA 02142, USA

^e Neuroscience Institute, NYU Grossman School of Medicine, New York, NY 10016, USA

^f Department of Neurobiology, Stanford University, Stanford, CA 94305, USA

^g Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA

^h Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA

ⁱ Department of Neuroscience & Physiology, NYU Grossman School of Medicine, New York, NY 10016, USA

^j Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY 10016, USA

^k Purdue Institute for Drug Discovery, 720 Clinic Drive, West Lafayette, IN 47907, USA

^l Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA

^m Purdue Institute of Inflammation, Immunology and Infectious Disease, Purdue University, West Lafayette, IN 47907, USA

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 Aβ_1–42 analogue (Aβ^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 Aβ^pH in real time in live animals. We find that microglia phagocytose more Aβ^pH than astrocytes in culture, in brain slices and in vivo. Aβ^pH 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.

Chemical Science

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

Abstract

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

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