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Microglia degrade Alzheimer's amyloid-beta deposits extracellularly via digestive exophagy

Jacquet, Rudy G ; González Ibáñez, Fernando ; Picard, Katherine ; Funes, Lucy ; Khakpour, Mohammadparsa ; Gouras, Gunnar K LU orcid ; Tremblay, Marie-Ève ; Maxfield, Frederick R and Solé-Domènech, Santiago LU (2024) In Cell Reports 43(12).
Abstract

How microglia digest Alzheimer's fibrillar amyloid-beta (Aβ) plaques that are too large to be phagocytosed is not well understood. Here, we show that primary microglial cells create acidic extracellular compartments, lysosomal synapses, on model plaques and digest them with exocytosed lysosomal enzymes. This mechanism, called digestive exophagy, is confirmed by electron microscopy in 5xFAD mouse brains, which shows that a lysosomal enzyme, acid phosphatase, is secreted toward the plaques in structures resembling lysosomal synapses. Signaling studies demonstrate that the PI3K-AKT pathway modulates the formation of lysosomal synapses, as inhibition of PI3K1β or AKT1/2 reduces both lysosome exocytosis and actin polymerization, both... (More)

How microglia digest Alzheimer's fibrillar amyloid-beta (Aβ) plaques that are too large to be phagocytosed is not well understood. Here, we show that primary microglial cells create acidic extracellular compartments, lysosomal synapses, on model plaques and digest them with exocytosed lysosomal enzymes. This mechanism, called digestive exophagy, is confirmed by electron microscopy in 5xFAD mouse brains, which shows that a lysosomal enzyme, acid phosphatase, is secreted toward the plaques in structures resembling lysosomal synapses. Signaling studies demonstrate that the PI3K-AKT pathway modulates the formation of lysosomal synapses, as inhibition of PI3K1β or AKT1/2 reduces both lysosome exocytosis and actin polymerization, both required for the formation of the compartments. Finally, we show that small fibrils of Aβ previously internalized and trafficked to lysosomes are exocytosed toward large Aβ aggregates by microglia. Thus, the release of lysosomal contents during digestive exophagy may also contribute to the spread and growth of fibrillar Aβ.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cell Reports
volume
43
issue
12
article number
115052
publisher
Cell Press
external identifiers
  • scopus:85211157639
  • pmid:39644493
ISSN
2211-1247
DOI
10.1016/j.celrep.2024.115052
language
English
LU publication?
yes
additional info
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.
id
e1571bea-875a-4ef8-bc54-52970eb4389d
date added to LUP
2024-12-11 10:31:42
date last changed
2025-06-09 21:34:40
@article{e1571bea-875a-4ef8-bc54-52970eb4389d,
  abstract     = {{<p>How microglia digest Alzheimer's fibrillar amyloid-beta (Aβ) plaques that are too large to be phagocytosed is not well understood. Here, we show that primary microglial cells create acidic extracellular compartments, lysosomal synapses, on model plaques and digest them with exocytosed lysosomal enzymes. This mechanism, called digestive exophagy, is confirmed by electron microscopy in 5xFAD mouse brains, which shows that a lysosomal enzyme, acid phosphatase, is secreted toward the plaques in structures resembling lysosomal synapses. Signaling studies demonstrate that the PI3K-AKT pathway modulates the formation of lysosomal synapses, as inhibition of PI3K1β or AKT1/2 reduces both lysosome exocytosis and actin polymerization, both required for the formation of the compartments. Finally, we show that small fibrils of Aβ previously internalized and trafficked to lysosomes are exocytosed toward large Aβ aggregates by microglia. Thus, the release of lysosomal contents during digestive exophagy may also contribute to the spread and growth of fibrillar Aβ.</p>}},
  author       = {{Jacquet, Rudy G and González Ibáñez, Fernando and Picard, Katherine and Funes, Lucy and Khakpour, Mohammadparsa and Gouras, Gunnar K and Tremblay, Marie-Ève and Maxfield, Frederick R and Solé-Domènech, Santiago}},
  issn         = {{2211-1247}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{12}},
  publisher    = {{Cell Press}},
  series       = {{Cell Reports}},
  title        = {{Microglia degrade Alzheimer's amyloid-beta deposits extracellularly via digestive exophagy}},
  url          = {{http://dx.doi.org/10.1016/j.celrep.2024.115052}},
  doi          = {{10.1016/j.celrep.2024.115052}},
  volume       = {{43}},
  year         = {{2024}},
}