Loss of lamin‐B1 and defective nuclear morphology are hallmarks of astrocyte senescence in vitro and in the aging human hippocampus

作者：Isadora C. Pereira Matias, Luan Pereira Diniz, Isabella Vivarini Damico, Ana Paula Bérgamo Araújo, Laís da Silva Neves, Gabriele Vargas, Renata Elaine Paraízo Leite, Cláudia Kimie Suemoto, Ricardo Nitríni, Wilson Jacob Filho, Lea T. Grinberg, Elly M. Hol, Jinte Middeldorp, Flávia Carvalho Alcântara Gomes · 发表于：Aging Cell · 年份：2021 · DOI：10.1111/acel.13521 · 被引用次数：188 · 研究领域：Nuclear Structure and Function、Telomeres, Telomerase, and Senescence、RNA Interference and Gene Delivery

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 as...