Astroglial morphological alterations associated with loss of nuclear S100A10 in the hippocampus of male tree shrews during aging

Astrocytes are glial cells that participate in multiple physiological functions, including protecting neurons against damage. However, some astrocytes undergo morphological alterations during aging, such as changes in process length and complexity. These morphological changes impact the astrocyte´s physiological functions. To better understand astrocyte alterations during aging, we used a long-lived animal, the tree shrew ( Tupaia belangeri ). Adult (3.8 years old, yo) and old (7 yo) male tree shrews were used to analyze the morphology of GFAP + astrocytes in the hippocampal formation. The total number of GFAP + astrocytes was similar between adult and old tree shrews in different hippocampal sub-regions. However, in the dentate gyrus (DG) and CA2-CA1, astrocytes had an increased process length in old animals compared to adults, denoting a hypertrophic phenotype. On the contrary, in CA3, astrocytes had an atrophic phenotype in old animals. Increased oxidative RNA damage was found in most astrocytes across all sub-regions analyzed during aging. S100A10, a protein overexpressed by astrocytes with a neuroprotective function, was primarily found in the nucleus of hypertrophic astrocytes in adult and elderly subjects, except in the subiculum (SUB). In old animals, a lack of S100A10, or S100A10 located in the cytoplasmic compartment along Crm-1 (transnuclear membrane protein that facilitates the transport of multiple proteins), characterized the atrophic GFAP + phenotype. These results demonstrate that tree shrews exhibit distinct astroglial morphological alterations in the hippocampal subregions during aging, and the transport of S100A10 from the nucleus to the cytoplasmic compartment may be related to the process of atrophy in astrocytes. Loss of nuclear S100A10 in the hippocampus of aged tree shrew. A. In adult subjects, most GFAP + astrocytes exhibit a hypertrophic morphology, and S100A10 (red rhombus) is localized in the nuclear compartment adjacent to Crm-1 (blue triangles). B. In old tree shrews, RNA oxidation (8OHG) was heavily observed around the nucleus, but lack of S100A10 or its location in the cytoplasm with Crm-1 featured the atrophic astrocytes. Created with BioRender.com • Reactive astrocytes increased in old subjects, followed by atrophic astrocytes in aged animals. • Oxidized RNA affects all types of astrocytes in old and aged tree shrews. • In old and aged animals, astrocytes lacking nuclear S1001A10 are atrophic.