期刊
AGING CELL
卷 21, 期 1, 页码 -出版社
WILEY
DOI: 10.1111/acel.13521
关键词
aging; astrocyte; human and mouse hippocampus; lamin-B1; senescence; synapse
资金
- Instituto Nacional de Neurociencia Translacional
- U.S. Department of Health and Human Services
- Ministerio da Saude, Departamento de Ciencia e Tecnologia
- Fiocruz-MS-Servier Award
- ZonMW Memorabel and Alzheimer Nederland
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior
- Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo
The reduction of lamin-B1 is a hallmark of senescent astrocytes contributing to nuclear deformations, which are found in aged mouse brains and post-mortem human brain tissue. This study suggests a regional-dependent aging response of human astrocytes in the hippocampus, with implications for impaired astrocyte functions during aging.
The increase in senescent cells in tissues, including the brain, is a general feature of normal aging and age-related pathologies. Senescent cells exhibit a specific phenotype, which includes an altered nuclear morphology and transcriptomic changes. Astrocytes undergo senescence in vitro and in age-associated neurodegenerative diseases, but little is known about whether this process also occurs in physiological aging, as well as its functional implication. Here, we investigated astrocyte senescence in vitro, in old mouse brains, and in post-mortem human brain tissue of elderly. We identified a significant loss of lamin-B1, a major component of the nuclear lamina, as a hallmark of senescent astrocytes. We showed a severe reduction of lamin-B1 in the dentate gyrus of aged mice, including in hippocampal astrocytes, and in the granular cell layer of the hippocampus of post-mortem human tissue from non-demented elderly. The lamin-B1 reduction was associated with nuclear deformations, represented by an increased incidence of invaginated nuclei and loss of nuclear circularity in senescent astrocytes in vitro and in the aging human hippocampus. We also found differences in lamin-B1 levels and astrocyte nuclear morphology between the granular cell layer and polymorphic layer in the elderly human hippocampus, suggesting an intra-regional-dependent aging response of human astrocytes. Moreover, we described senescence-associated impaired neuritogenic and synaptogenic capacity of mouse astrocytes. Our findings show that reduction of lamin-B1 is a conserved feature of hippocampal cells aging, including astrocytes, and shed light on significant defects in nuclear lamina structure which may contribute to astrocyte dysfunctions during aging.
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