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Myeloid deficiency of the intrinsic clock protein BMAL1 accelerates cognitive aging by disrupting microglial synaptic pruning
Aging is associated with loss of circadian immune responses and circadian gene transcription in peripheral macrophages. Microglia, the resident macrophages of the brain, also show diurnal rhythmicity in regulating local immune responses and synaptic remodeling. To investigate the interaction between...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9951430/ https://www.ncbi.nlm.nih.gov/pubmed/36829230 http://dx.doi.org/10.1186/s12974-023-02727-8 |
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author | Iweka, Chinyere Agbaegbu Seigneur, Erica Hernandez, Amira Latif Paredes, Sur Herrera Cabrera, Mica Blacher, Eran Pasternak, Connie Tsai Longo, Frank M. de Lecea, Luis Andreasson, Katrin I. |
author_facet | Iweka, Chinyere Agbaegbu Seigneur, Erica Hernandez, Amira Latif Paredes, Sur Herrera Cabrera, Mica Blacher, Eran Pasternak, Connie Tsai Longo, Frank M. de Lecea, Luis Andreasson, Katrin I. |
author_sort | Iweka, Chinyere Agbaegbu |
collection | PubMed |
description | Aging is associated with loss of circadian immune responses and circadian gene transcription in peripheral macrophages. Microglia, the resident macrophages of the brain, also show diurnal rhythmicity in regulating local immune responses and synaptic remodeling. To investigate the interaction between aging and microglial circadian rhythmicity, we examined mice deficient in the core clock transcription factor, BMAL1. Aging Cd11b(cre);Bmal(lox/lox) mice demonstrated accelerated cognitive decline in association with suppressed hippocampal long-term potentiation and increases in immature dendritic spines. C1q deposition at synapses and synaptic engulfment were significantly decreased in aging Bmal1-deficient microglia, suggesting that BMAL1 plays a role in regulating synaptic pruning in aging. In addition to accelerated age-associated hippocampal deficits, Cd11b(cre);Bmal(lox/lox) mice also showed deficits in the sleep–wake cycle with increased wakefulness across light and dark phases. These results highlight an essential role of microglial BMAL1 in maintenance of synapse homeostasis in the aging brain. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02727-8. |
format | Online Article Text |
id | pubmed-9951430 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-99514302023-02-25 Myeloid deficiency of the intrinsic clock protein BMAL1 accelerates cognitive aging by disrupting microglial synaptic pruning Iweka, Chinyere Agbaegbu Seigneur, Erica Hernandez, Amira Latif Paredes, Sur Herrera Cabrera, Mica Blacher, Eran Pasternak, Connie Tsai Longo, Frank M. de Lecea, Luis Andreasson, Katrin I. J Neuroinflammation Research Aging is associated with loss of circadian immune responses and circadian gene transcription in peripheral macrophages. Microglia, the resident macrophages of the brain, also show diurnal rhythmicity in regulating local immune responses and synaptic remodeling. To investigate the interaction between aging and microglial circadian rhythmicity, we examined mice deficient in the core clock transcription factor, BMAL1. Aging Cd11b(cre);Bmal(lox/lox) mice demonstrated accelerated cognitive decline in association with suppressed hippocampal long-term potentiation and increases in immature dendritic spines. C1q deposition at synapses and synaptic engulfment were significantly decreased in aging Bmal1-deficient microglia, suggesting that BMAL1 plays a role in regulating synaptic pruning in aging. In addition to accelerated age-associated hippocampal deficits, Cd11b(cre);Bmal(lox/lox) mice also showed deficits in the sleep–wake cycle with increased wakefulness across light and dark phases. These results highlight an essential role of microglial BMAL1 in maintenance of synapse homeostasis in the aging brain. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02727-8. BioMed Central 2023-02-24 /pmc/articles/PMC9951430/ /pubmed/36829230 http://dx.doi.org/10.1186/s12974-023-02727-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Iweka, Chinyere Agbaegbu Seigneur, Erica Hernandez, Amira Latif Paredes, Sur Herrera Cabrera, Mica Blacher, Eran Pasternak, Connie Tsai Longo, Frank M. de Lecea, Luis Andreasson, Katrin I. Myeloid deficiency of the intrinsic clock protein BMAL1 accelerates cognitive aging by disrupting microglial synaptic pruning |
title | Myeloid deficiency of the intrinsic clock protein BMAL1 accelerates cognitive aging by disrupting microglial synaptic pruning |
title_full | Myeloid deficiency of the intrinsic clock protein BMAL1 accelerates cognitive aging by disrupting microglial synaptic pruning |
title_fullStr | Myeloid deficiency of the intrinsic clock protein BMAL1 accelerates cognitive aging by disrupting microglial synaptic pruning |
title_full_unstemmed | Myeloid deficiency of the intrinsic clock protein BMAL1 accelerates cognitive aging by disrupting microglial synaptic pruning |
title_short | Myeloid deficiency of the intrinsic clock protein BMAL1 accelerates cognitive aging by disrupting microglial synaptic pruning |
title_sort | myeloid deficiency of the intrinsic clock protein bmal1 accelerates cognitive aging by disrupting microglial synaptic pruning |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9951430/ https://www.ncbi.nlm.nih.gov/pubmed/36829230 http://dx.doi.org/10.1186/s12974-023-02727-8 |
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