Myeloid deficiency of the intrinsic clock protein BMAL1 accelerates cognitive aging by disrupting microglial synaptic pruning
Abstract 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 interactio...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-02-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-023-02727-8 |
| _version_ | 1797864010841849856 |
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| author | Chinyere Agbaegbu Iweka Erica Seigneur Amira Latif Hernandez Sur Herrera Paredes Mica Cabrera Eran Blacher Connie Tsai Pasternak Frank M. Longo Luis de Lecea Katrin I. Andreasson |
| author_facet | Chinyere Agbaegbu Iweka Erica Seigneur Amira Latif Hernandez Sur Herrera Paredes Mica Cabrera Eran Blacher Connie Tsai Pasternak Frank M. Longo Luis de Lecea Katrin I. Andreasson |
| author_sort | Chinyere Agbaegbu Iweka |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-09T22:44:44Z |
| format | Article |
| id | doaj.art-4c1d1881d39f43bcacd644ecfab69692 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-09T22:44:44Z |
| publishDate | 2023-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-4c1d1881d39f43bcacd644ecfab696922023-03-22T11:54:59ZengBMCJournal of Neuroinflammation1742-20942023-02-0120111610.1186/s12974-023-02727-8Myeloid deficiency of the intrinsic clock protein BMAL1 accelerates cognitive aging by disrupting microglial synaptic pruningChinyere Agbaegbu Iweka0Erica Seigneur1Amira Latif Hernandez2Sur Herrera Paredes3Mica Cabrera4Eran Blacher5Connie Tsai Pasternak6Frank M. Longo7Luis de Lecea8Katrin I. Andreasson9Department of Neurology and Neurological Sciences, Stanford School of MedicineDepartment of Psychiatry and Behavioral Sciences, Stanford UniversityDepartment of Neurology and Neurological Sciences, Stanford School of MedicineDepartment of Biology, Stanford UniversityDepartment of Neurology and Neurological Sciences, Stanford School of MedicineDepartment of Neurology and Neurological Sciences, Stanford School of MedicineDepartment of Neurology and Neurological Sciences, Stanford School of MedicineDepartment of Neurology and Neurological Sciences, Stanford School of MedicineDepartment of Psychiatry and Behavioral Sciences, Stanford UniversityDepartment of Neurology and Neurological Sciences, Stanford School of MedicineAbstract 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.https://doi.org/10.1186/s12974-023-02727-8Circadian clockBMAL1MicrogliaSynaptic plasticitySleep–wake cycle |
| spellingShingle | Chinyere Agbaegbu Iweka Erica Seigneur Amira Latif Hernandez Sur Herrera Paredes Mica Cabrera Eran Blacher Connie Tsai Pasternak Frank M. Longo Luis de Lecea Katrin I. Andreasson Myeloid deficiency of the intrinsic clock protein BMAL1 accelerates cognitive aging by disrupting microglial synaptic pruning Journal of Neuroinflammation Circadian clock BMAL1 Microglia Synaptic plasticity Sleep–wake cycle |
| 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 | Circadian clock BMAL1 Microglia Synaptic plasticity Sleep–wake cycle |
| url | https://doi.org/10.1186/s12974-023-02727-8 |
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