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Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology

Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology
Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology
The sustained proliferation of microglia is a key hallmark of Alzheimer’s disease (AD), accelerating its progression. Here, we sought to understand the long-term impact of the early and prolonged microglial proliferation observed in AD, hypothesising that extensive and repeated cycling would engender a distinct transcriptional and phenotypic trajectory. We found that the early and sustained microglial proliferation seen in an AD-like model promotes replicative senescence, characterised by increased βgal activity, a senescence-associated transcriptional signature and telomere shortening, correlating with the appearance of disease-associated microglia (DAM) and senescent microglial profiles in human post-mortem AD cases. Prevention of early microglial proliferation hindered the development of senescence and DAM, impairing the accumulation of Aβ and associated neuritic damage. Overall, our results support that excessive microglial proliferation leads to the generation of senescent DAM, which contribute to early Aβ pathology in AD.
2211-1247
Hu, Yanling
b116f116-780e-40eb-893f-ca04c2d8f9a8
Fryatt, Gemma Louise
afd66d34-31f7-4231-9a7c-50bc283646bd
Ghorbani, Mohammadmersad
eb86b6b9-6151-4b32-bfea-c56ff6ad31c9
Obst, Juliane
0c499ee6-0290-4792-8c99-049e05332227
Menassa, David
eeb394a6-c72b-49d7-a820-95b0256c22d5
Martin estebane, Maria
51e238f8-2ae3-4914-8e84-71f09e6b4f58
Muntslag, Tim Arno Othni
a19febb7-c244-4825-abad-a5e1d1aa80a9
Olmos alonso, Adrian
c52c3bd9-2cf0-4b55-9214-cb549449db75
Guerrero Carrasco, Monica
e390f2cf-db0f-49bf-aa4a-673b1fa8cc15
Thomas, Daniel
c78fb85f-7493-4150-ac47-c17caef5b3aa
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Gomez-Nicola, Diego
0680aa66-9dee-47cf-a8d3-e39c988f85b5
Hu, Yanling
b116f116-780e-40eb-893f-ca04c2d8f9a8
Fryatt, Gemma Louise
afd66d34-31f7-4231-9a7c-50bc283646bd
Ghorbani, Mohammadmersad
eb86b6b9-6151-4b32-bfea-c56ff6ad31c9
Obst, Juliane
0c499ee6-0290-4792-8c99-049e05332227
Menassa, David
eeb394a6-c72b-49d7-a820-95b0256c22d5
Martin estebane, Maria
51e238f8-2ae3-4914-8e84-71f09e6b4f58
Muntslag, Tim Arno Othni
a19febb7-c244-4825-abad-a5e1d1aa80a9
Olmos alonso, Adrian
c52c3bd9-2cf0-4b55-9214-cb549449db75
Guerrero Carrasco, Monica
e390f2cf-db0f-49bf-aa4a-673b1fa8cc15
Thomas, Daniel
c78fb85f-7493-4150-ac47-c17caef5b3aa
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Gomez-Nicola, Diego
0680aa66-9dee-47cf-a8d3-e39c988f85b5

Hu, Yanling, Fryatt, Gemma Louise, Ghorbani, Mohammadmersad, Obst, Juliane, Menassa, David, Martin estebane, Maria, Muntslag, Tim Arno Othni, Olmos alonso, Adrian, Guerrero Carrasco, Monica, Thomas, Daniel, Cragg, Mark and Gomez-Nicola, Diego (2021) Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology. Cell Reports. (doi:10.1101/2021.03.22.436174).

Record type: Article

Abstract

The sustained proliferation of microglia is a key hallmark of Alzheimer’s disease (AD), accelerating its progression. Here, we sought to understand the long-term impact of the early and prolonged microglial proliferation observed in AD, hypothesising that extensive and repeated cycling would engender a distinct transcriptional and phenotypic trajectory. We found that the early and sustained microglial proliferation seen in an AD-like model promotes replicative senescence, characterised by increased βgal activity, a senescence-associated transcriptional signature and telomere shortening, correlating with the appearance of disease-associated microglia (DAM) and senescent microglial profiles in human post-mortem AD cases. Prevention of early microglial proliferation hindered the development of senescence and DAM, impairing the accumulation of Aβ and associated neuritic damage. Overall, our results support that excessive microglial proliferation leads to the generation of senescent DAM, which contribute to early Aβ pathology in AD.

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More information

Published date: 8 June 2021

Identifiers

Local EPrints ID: 449756
URI: http://eprints.soton.ac.uk/id/eprint/449756
ISSN: 2211-1247
PURE UUID: ee071cdd-7601-437d-a18e-acae74cacf27
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X
ORCID for Diego Gomez-Nicola: ORCID iD orcid.org/0000-0002-5316-2682

Catalogue record

Date deposited: 16 Jun 2021 16:30
Last modified: 17 Jun 2021 01:42

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Contributors

Author: Yanling Hu
Author: Mohammadmersad Ghorbani
Author: Juliane Obst
Author: David Menassa
Author: Maria Martin estebane
Author: Tim Arno Othni Muntslag
Author: Adrian Olmos alonso
Author: Daniel Thomas
Author: Mark Cragg ORCID iD

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