Premature aging of the hippocampal neurogenic niche in adult Bmal1‐ deficient mice

Ali, Amira A. H.; Schwarz-Herzke, Beryl; Stahr, Anna; Prozorovski, Timour; Aktaş, Orhan; Gall, Charlotte von

doi:10.18632/aging.100764

Cited by 49 publications

(49 citation statements)

References 73 publications

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“…The identification of proliferating and apoptotic cells as undertaken in the present study extends previous data on neurogenesis (Steiner et al, ; Ali et al, ), gliogenesis (Cameron et al, ; Bondolfi et al, ; Steiner et al, ; Sierra et al, ; Matsumoto et al, ), and angiogenesis (Sierra et al, ), but also on apoptosis of different cell types (Sierra et al, ) in the adult hippocampus. Except for neurons, all other cell types did not display day–night differences in proliferation and apoptosis in the hippocampal subregions investigated.…”

Section: Discussionsupporting

confidence: 87%

Impact of melatonin receptor‐signaling on Zeitgeber time‐dependent changes in cell proliferation and apoptosis in the adult murine hippocampus

et al. 2017

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The hippocampus is subjected to diurnal/circadian rhythms on both the morphological and molecular levels. Certain aspects of cell proliferation in the adult hippocampus are regulated by melatonin and accompanied by apoptosis to ensure proper tissue maintenance and function. The present study investigated Zeitgeber time (ZT)-dependent changes in cell proliferation and apoptosis in the adult murine hippocampus and their regulation by melatonin receptor type1 and type2 (MT1/2)-mediated signaling. Adult melatonin-proficient C3H/HeN mice and melatonin-proficient (C3H/HeN) mice with targeted deletion of MT1/2 were adapted to a 12-h light, 12-h dark photoperiod and were sacrificed at ZT00, ZT06, ZT12, and ZT18. Immunohistochemistry for Ki67 and activated caspase-3 in combination with different markers for the diverse cell types residing in the hippocampus served to identify and quantify proliferating and apoptotic cells in the hippocampal subregions. ZT-dependent changes in cell proliferation and apoptosis were found exclusively in the subgranular zone (SGZ) and granule cell layer (GCL) of melatonin-proficient mice with functional MT1/2. Cell proliferation in the SGZ showed ZT-dependent changes indicated by an increase of proliferating immature neurons during the dark phase of the 24-h light-dark cycle. Apoptosis showed ZT-dependent changes in the SGZ and GCL indicated by an increase of apoptotic immature neurons at ZT06 (SGZ) and a decrease of immature and mature neurons at ZT18 (GCL). Our results indicate that ZT-dependent changes in proliferation of immature neurons in the SGZ are counterbalanced by ZT-dependent changes in apoptosis of immature and mature neurons in the SGZ and GCL exclusively in mice with functional MT1/2. Therefore, MT1/2-mediated signaling appears to be crucial for generation and timing of ZT-dependent changes in cell proliferation and apoptosis and for differentiation of proliferating cells into neurons in the SGZ. © 2017 Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 87%

Impact of melatonin receptor‐signaling on Zeitgeber time‐dependent changes in cell proliferation and apoptosis in the adult murine hippocampus

et al. 2017

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“…Bmal1 deficient mice develop striking neurological phenotypes, including profound spontaneous astrogliosis, increased oxidative damage, synaptic degeneration, impaired brain functional connectivity (12), impaired learning and memory (60), altered hippocampal neurogenesis (76–78), and lowered seizure threshold (79). In some of these cases, it remains unclear if the phenotype is due to loss of Bmal1 in the cells of the brain itself, or secondary to whole-animal changes in metabolism.…”

Section: Disrupted Cellular Clocks and Neurodegenerationmentioning

confidence: 99%

Mechanisms linking circadian clocks, sleep, and neurodegeneration

Musiek

Holtzman

2016

Science

588

498

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Disruption of normal circadian rhythms and sleep cycles are consequences of aging and can profoundly impact health. Accumulating evidence indicates that circadian and sleep disturbances, which have long been considered symptoms of many neurodegenerative conditions, may actually drive pathogenesis early in the course of these diseases. In this review we explore potential cellular and molecular mechanisms linking circadian dysfunction and sleep loss to neurodegenerative diseases, with a focus on Alzheimer’s Disease. We examine the interplay between central and peripheral circadian rhythms, circadian clock gene function, and sleep in maintaining brain homeostasis, and discuss therapeutic implications. The circadian clock and sleep can influence a number of key processes involved in neurodegeneration, suggesting that these systems might be manipulated to promote healthy brain aging.

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“…Bmal1−/− mice have a significantly reduced lifespan and show signs of accelerated ageing such as sarcopenia, cataracts, less subcutaneous fat, organ shrinkage by 16-18 weeks of age, presumably as a consequence of highly elevated levels of reactive oxygen species (ROS) (Kondratov, Kondratova, Gorbacheva, Vykhovanets, & Antoch, 2006). Moreover, Bmal1−/− mice exhibit severe cognitive deficits (Kondratov et al, 2006;Kondratova, Dubrovsky, Antoch, & Kondratov, 2010) and impaired adult neurogenesis (Ali et al, 2015;Ali et al, 2018;Bouchard-Cannon, Mendoza-Viveros, Yuen, Kaern, & Cheng, 2013). In the brain of 10-15 weeks old Bmal1−/− mice astrocytosis starts to develop, as evidenced by an increased expression of glial fibrillary acidic protein (GFAP) (Musiek et al, 2013) and by the age of 24 weeks, synaptic terminals are degenerated and cortical functional connectivity is affected (Musiek et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Bmal1‐deficiency affects glial synaptic coverage of the hippocampal mossy fiber synapse and the actin cytoskeleton in astrocytes

Ali

Schwarz-Herzke

Rollenhagen

et al. 2019

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Bmal1 is an essential component of the molecular clockwork, which drives circadian rhythms in cell function. In Bmal1‐deficient (Bmal1−/−) mice, chronodisruption is associated with cognitive deficits and progressive brain pathology including astrocytosis indicated by increased expression of glial fibrillary acidic protein (GFAP). However, relatively little is known about the impact of Bmal1‐deficiency on astrocyte morphology prior to astrocytosis. Therefore, in this study we analysed astrocyte morphology in young (6–8 weeks old) adult Bmal1−/− mice. At this age, overall GFAP immunoreactivity was not increased in Bmal1‐deficient mice. At the ultrastructural level, we found a decrease in the volume fraction of the fine astrocytic processes that cover the hippocampal mossy fiber synapse, suggesting an impairment of perisynaptic processes and their contribution to neurotransmission. For further analyses of actin cytoskeleton, which is essential for distal process formation, we used cultured Bmal1−/− astrocytes. Bmal1−/− astrocytes showed an impaired formation of actin stress fibers. Moreover, Bmal1−/− astrocytes showed reduced levels of the actin‐binding protein cortactin (CTTN). Cttn promoter region contains an E‐Box like element and chromatin immunoprecipitation revealed that Cttn is a potential Bmal1 target gene. In addition, the level of GTP‐bound (active) Rho‐GTPase (Rho‐GTP) was reduced in Bmal1−/− astrocytes. In summary, our data demonstrate that Bmal1‐deficiency affects morphology of the fine astrocyte processes prior to strong upregulation of GFAP, presumably because of impaired Cttn expression and reduced Rho‐GTP activation. These morphological changes might result in altered synaptic function and, thereby, relate to cognitive deficits in chronodisruption.

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Premature aging of the hippocampal neurogenic niche in adult Bmal1‐ deficient mice

Cited by 49 publications

References 73 publications

Impact of melatonin receptor‐signaling on Zeitgeber time‐dependent changes in cell proliferation and apoptosis in the adult murine hippocampus

Impact of melatonin receptor‐signaling on Zeitgeber time‐dependent changes in cell proliferation and apoptosis in the adult murine hippocampus

Mechanisms linking circadian clocks, sleep, and neurodegeneration

Bmal1‐deficiency affects glial synaptic coverage of the hippocampal mossy fiber synapse and the actin cytoskeleton in astrocytes

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