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P2Y(6) receptor‐dependent microglial phagocytosis of synapses mediates synaptic and memory loss in aging
Aging causes loss of brain synapses and memory, and microglial phagocytosis of synapses may contribute to this loss. Stressed neurons can release the nucleotide UTP, which is rapidly converted into UDP, that in turn activates the P2Y(6) receptor (P2Y(6)R) on the surface of microglia, inducing microg...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9924939/ https://www.ncbi.nlm.nih.gov/pubmed/36565471 http://dx.doi.org/10.1111/acel.13761 |
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author | Dundee, Jacob M. Puigdellívol, Mar Butler, Richard Cockram, Thomas O. J. Brown, Guy C. |
author_facet | Dundee, Jacob M. Puigdellívol, Mar Butler, Richard Cockram, Thomas O. J. Brown, Guy C. |
author_sort | Dundee, Jacob M. |
collection | PubMed |
description | Aging causes loss of brain synapses and memory, and microglial phagocytosis of synapses may contribute to this loss. Stressed neurons can release the nucleotide UTP, which is rapidly converted into UDP, that in turn activates the P2Y(6) receptor (P2Y(6)R) on the surface of microglia, inducing microglial phagocytosis of neurons. However, whether the activation of P2Y(6)R affects microglial phagocytosis of synapses is unknown. We show here that inactivation of P2Y(6)R decreases microglial phagocytosis of isolated synapses (synaptosomes) and synaptic loss in neuronal–glial co‐cultures. In vivo, wild‐type mice aged from 4 to 17 months exhibited reduced synaptic density in cortical and hippocampal regions, which correlated with increased internalization of synaptic material within microglia. However, this aging‐induced synaptic loss and internalization were absent in P2Y(6)R knockout mice, and these mice also lacked any aging‐induced memory loss. Thus, P2Y(6)R appears to mediate aging‐induced loss of synapses and memory by increasing microglial phagocytosis of synapses. Consequently, blocking P2Y(6)R has the potential to prevent age‐associated memory impairment. |
format | Online Article Text |
id | pubmed-9924939 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-99249392023-02-14 P2Y(6) receptor‐dependent microglial phagocytosis of synapses mediates synaptic and memory loss in aging Dundee, Jacob M. Puigdellívol, Mar Butler, Richard Cockram, Thomas O. J. Brown, Guy C. Aging Cell Research Articles Aging causes loss of brain synapses and memory, and microglial phagocytosis of synapses may contribute to this loss. Stressed neurons can release the nucleotide UTP, which is rapidly converted into UDP, that in turn activates the P2Y(6) receptor (P2Y(6)R) on the surface of microglia, inducing microglial phagocytosis of neurons. However, whether the activation of P2Y(6)R affects microglial phagocytosis of synapses is unknown. We show here that inactivation of P2Y(6)R decreases microglial phagocytosis of isolated synapses (synaptosomes) and synaptic loss in neuronal–glial co‐cultures. In vivo, wild‐type mice aged from 4 to 17 months exhibited reduced synaptic density in cortical and hippocampal regions, which correlated with increased internalization of synaptic material within microglia. However, this aging‐induced synaptic loss and internalization were absent in P2Y(6)R knockout mice, and these mice also lacked any aging‐induced memory loss. Thus, P2Y(6)R appears to mediate aging‐induced loss of synapses and memory by increasing microglial phagocytosis of synapses. Consequently, blocking P2Y(6)R has the potential to prevent age‐associated memory impairment. John Wiley and Sons Inc. 2022-12-24 /pmc/articles/PMC9924939/ /pubmed/36565471 http://dx.doi.org/10.1111/acel.13761 Text en © 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Dundee, Jacob M. Puigdellívol, Mar Butler, Richard Cockram, Thomas O. J. Brown, Guy C. P2Y(6) receptor‐dependent microglial phagocytosis of synapses mediates synaptic and memory loss in aging |
title |
P2Y(6)
receptor‐dependent microglial phagocytosis of synapses mediates synaptic and memory loss in aging |
title_full |
P2Y(6)
receptor‐dependent microglial phagocytosis of synapses mediates synaptic and memory loss in aging |
title_fullStr |
P2Y(6)
receptor‐dependent microglial phagocytosis of synapses mediates synaptic and memory loss in aging |
title_full_unstemmed |
P2Y(6)
receptor‐dependent microglial phagocytosis of synapses mediates synaptic and memory loss in aging |
title_short |
P2Y(6)
receptor‐dependent microglial phagocytosis of synapses mediates synaptic and memory loss in aging |
title_sort | p2y(6)
receptor‐dependent microglial phagocytosis of synapses mediates synaptic and memory loss in aging |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9924939/ https://www.ncbi.nlm.nih.gov/pubmed/36565471 http://dx.doi.org/10.1111/acel.13761 |
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