Age-related changes in the structure and composition of the nuclear envelope and surrounding cytoskeleton of murine and human astrocytes

Brain aging is associated with the accumulation of senescent cells that exhibit transcriptomic, morphological, and functional alterations. Our group has previously shown that senescent astrocytes have decreased content of lamin-B1 and increased proportion of nuclear deformations in vitro and in vivo. However, little is known about the structure and composition of the nuclear envelope in senescent astrocytes during normal aging. To further investigate these senescence-related changes, we used an in vitro model of murine astrocytic senescence (long-term cultures (30-35 DIV) compared to control cultures (7-10 DIV)), hippocampal samples from young (2-5 months old) and aged (≥18 months old) C57BL/6 mice, and post-mortem human hippocampal tissues from middle-aged (40-50 years old) and elderly individuals (80-100 years old). Here, we showed upregulation of lamin-B2, a lamin subtype homolog to lamin-B1, in senescent astrocytes in vitro. Interestingly, a higher proportion of lamin-B2 positive astrocytes was also observed in the hippocampal dentate gyrus of aged mice and in the post-mortem tissues of elderly donors compared to the younger controls. In addition, cultured senescent astrocytes showed a two-fold increase in the level of SUN-1, a protein of the Linker Nucleoskeleton and Cytoskeleton (LINC) complex, and in the number of nuclei containing invaginated γ-tubulin inclusion. Therefore, our data suggest that astrocyte senescence is associated with modulation of the nuclear lamina structure, upregulation of LINC complex components, and mislocalization of γ-tubulin, which might affect nuclear envelope integrity and function during aging.

Support: CNPq, CAPES, FAPERJ, DECIT-Ministério da Saúde, Instituto Nacional de Neurociência Translacional.