Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Dundee, Jacob M., Puigdellívol, Mar, Butler, Richard, Cockram, Thomas O. J., Brown, Guy C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
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
_version_ 1784887957769945088
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
work_keys_str_mv AT dundeejacobm p2y6receptordependentmicroglialphagocytosisofsynapsesmediatessynapticandmemorylossinaging
AT puigdellivolmar p2y6receptordependentmicroglialphagocytosisofsynapsesmediatessynapticandmemorylossinaging
AT butlerrichard p2y6receptordependentmicroglialphagocytosisofsynapsesmediatessynapticandmemorylossinaging
AT cockramthomasoj p2y6receptordependentmicroglialphagocytosisofsynapsesmediatessynapticandmemorylossinaging
AT brownguyc p2y6receptordependentmicroglialphagocytosisofsynapsesmediatessynapticandmemorylossinaging