Abstract:Aging can cause morphological transformation in human microglia indicative of cell senescence, termed microglial dystrophy. However, cellular senescence is characterized by additional changes, such as an irregular cell cycle arrest, and a variety of metabolic and molecular changes including a senescence-associated secretory phenotype, dysfunction of degradation mechanisms, and altered DNA damage response. Here, we tested whether dystrophic microglia display customary markers of cell senescence by performing do… Show more
“…While it is not significantly enriched in any individual spatial domain comprising the DG, it is enriched in the composite DG in the elderly group ( Table S3 ). Inflammatory stimuli can induce iron accumulation in microglia and neurons in vitro via hepcidin and related molecules 74 , which is important because iron overloading is consistently observed in aging microglia that express a senescent or dystrophic phenotype 51,52 .…”
Section: Resultsmentioning
confidence: 99%
“…Inflammation is associated with blood-brain barrier (BBB) permeability, and human functional magnetic resonance imaging (fMRI) studies suggest pronounced aging-related increases in BBB permeability at the DG 34 . In aged rodents, neuroblasts adopt a senescence-associated secretory phenotype that induces auto-inflammation 35 , while glial cells, including microglia and astrocytes, undergo age-dependent increases in neuroinflammation in the DG, which decreases neurogenesis and exacerbates degeneration 33,[36][37][38][39][40][41][42][43][44] . Importantly, activated microglia can induce reactive astrocytes 39 , triggering further inflammation and neurodegeneration.…”
The dentate gyrus of the anterior hippocampus is important for many human cognitive functions, including regulation of learning, memory, and mood. However, the postnatal development and aging of the dentate gyrus throughout the human lifespan has yet to be fully characterized in the same molecular and spatial detail as other species. Here, we generated a spatially-resolved molecular atlas of the dentate gyrus in postmortem human tissue using the 10x Genomics Visium platform to retain extranuclear transcripts and identify changes in molecular topography across the postnatal lifespan. We found enriched expression of extracellular matrix markers during infancy and increased expression of GABAergic cell-type markersGAD1,LAMP5,andCCKafter infancy. While we identified a conserved gene signature for mouse neuroblasts in the granule cell layer (GCL), many of those genes are not specific to the GCL, and we found no evidence of signatures for other granule cell lineage stages at the GCL post-infancy. We identified a wide-spread hippocampal aging signature and an age-dependent increase in neuroinflammation associated genes. Our findings suggest major changes to the putative neurogenic niche after infancy and identify molecular foci of brain aging in glial and neuropil enriched tissue.
“…While it is not significantly enriched in any individual spatial domain comprising the DG, it is enriched in the composite DG in the elderly group ( Table S3 ). Inflammatory stimuli can induce iron accumulation in microglia and neurons in vitro via hepcidin and related molecules 74 , which is important because iron overloading is consistently observed in aging microglia that express a senescent or dystrophic phenotype 51,52 .…”
Section: Resultsmentioning
confidence: 99%
“…Inflammation is associated with blood-brain barrier (BBB) permeability, and human functional magnetic resonance imaging (fMRI) studies suggest pronounced aging-related increases in BBB permeability at the DG 34 . In aged rodents, neuroblasts adopt a senescence-associated secretory phenotype that induces auto-inflammation 35 , while glial cells, including microglia and astrocytes, undergo age-dependent increases in neuroinflammation in the DG, which decreases neurogenesis and exacerbates degeneration 33,[36][37][38][39][40][41][42][43][44] . Importantly, activated microglia can induce reactive astrocytes 39 , triggering further inflammation and neurodegeneration.…”
The dentate gyrus of the anterior hippocampus is important for many human cognitive functions, including regulation of learning, memory, and mood. However, the postnatal development and aging of the dentate gyrus throughout the human lifespan has yet to be fully characterized in the same molecular and spatial detail as other species. Here, we generated a spatially-resolved molecular atlas of the dentate gyrus in postmortem human tissue using the 10x Genomics Visium platform to retain extranuclear transcripts and identify changes in molecular topography across the postnatal lifespan. We found enriched expression of extracellular matrix markers during infancy and increased expression of GABAergic cell-type markersGAD1,LAMP5,andCCKafter infancy. While we identified a conserved gene signature for mouse neuroblasts in the granule cell layer (GCL), many of those genes are not specific to the GCL, and we found no evidence of signatures for other granule cell lineage stages at the GCL post-infancy. We identified a wide-spread hippocampal aging signature and an age-dependent increase in neuroinflammation associated genes. Our findings suggest major changes to the putative neurogenic niche after infancy and identify molecular foci of brain aging in glial and neuropil enriched tissue.
“…Microglia display substantial changes with aging, including changes in gene expression, ultrastructure, and the epigenome which affect their morphology, liposomal dysfunction (increased accumulation of lipofuscin and senescence-associated β-galoctosidase expression), and promote dysregulation of cell cycle protein machinery, including proteins p53, p21, and p14 Ink4a [reviewed in [28]]. These cells have been described in the literature as dystrophic or senescent and accumulate over time during normal brain aging [29]. Profound changes in transcriptional profiles with aging also result in secretion of various pro-inflammatory cytokines, a phenomenon referred to as senescence-associated secretory phenotype [28,30], characterized by increased secretion of IL-1, IL-6, and decreased secretion of various growth factors necessary for neuronal support.…”
Section: Age-related Changes In Microgliamentioning
Purpose of reviewMicroglia, which arise from primitive myeloid precursors that enter the central nervous system (CNS) during early development, are the first responders to any perturbance of homeostasis. Although their activation has become synonymous with neurologic disease, it remains unclear whether microglial responses are the cause of or response to neuropathology. Here, we review new insights in the roles of microglia during CNS health and disease, including preclinical studies that transcriptionally profile microglia to define their functional states.Recent findingsConverging evidence suggests that innate immune activation of microglia is associated with overlapping alterations in their gene expression profiles regardless of the trigger. Thus, recent studies examining neuroprotective microglial responses during infections and aging mirror those observed during chronic neurologic diseases, including neurodegeneration and stroke. Many of these insights derive from studies of microglial transcriptomes and function in preclinical models, some of which have been validated in human samples. During immune activation, microglia dismantle their homeostatic functions and transition into subsets capable of antigen presentation, phagocytosis of debris, and management of lipid homeostasis. These subsets can be identified during both normal and aberrant microglial responses, the latter of which may persist long-term. The loss of neuroprotective microglia, which maintain a variety of essential CNS functions, may therefore, in part, underlie the development of neurodegenerative diseases.SummaryMicroglia exhibit a high level of plasticity, transforming into numerous subsets as they respond to innate immune triggers. Chronic loss of microglial homeostatic functions may underlie the development of diseases with pathological forgetting.
“…In the healthy brain, microglia are the resident immune cells and are essential for proper brain functioning and homeostasis (6). However, microglia adopt a dystrophic morphology in postmortem brain samples from elderly donors (7)(8)(9). Additionally, in in vivo and in vitro mouse studies, microglia show defective functionality including reduced surveillance and phagocytic activity, increased production of reactive oxygen species (10,11), reduced response to insults (12), slower migration to sites of infection and processes shrinkage (13).…”
In response to various stressors, cells can enter a state called cellular senescence which is characterized by irreversible cell cycle arrest and a senescence-associated secretory phenotype (SASP). The progressive accumulation of senescent glial cells in the central nervous system (CNS) with aging suggests a potential role for senescence as driver of aging and inflammation in the brain. As the main immune cell population residing in the CNS, microglia are thought to play a pivotal role in the progression of age-associated neuroinflammation. Furthermore, due to their slow turnover, microglia are highly susceptible to undergoing cellular senescence. However, current understanding of age-related changes in microglia and their impact on brain aging is limited. Due to the challenge in accessing human primary microglia and the lack of models to adequately recapitulate aging, this knowledge is predominantly limited to rodent studies. Here, we chemically induced senescence in a human immortalized microglia cell line with a cocktail of senescence inducing molecules. We demonstrate that chemically induced senescent microglia adopt a pro-inflammatory phenotype, have reduced phagocytic activity and impaired calcium activity. Our results show that chemically induced senescence can mimic features of cellular aging and can provide insight on the impact of aging and cellular senescence on human microglia.
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