PAPP-A-Mediated Proteolytic Cleavage of IGFBP-4 and Age-Related Changes in the Primary Culture of Rat Astrocytes

The phenotype of “aging” nervous tissue, like other tissues, is associated with elevation of the quantity of senescent cells (SC), cells that have lost their ability to grow and divide. SC posess a special secretory phenotype known as SASP (Secretory Associated Senescence Phenotype), that includes pro-inflammatory cytokines, chemokines, and metalloproteases negatively affecting the microenvironment of these cells and provoking the development of neurodegeneration in the brain. Insulin-like growth factors-1 and 2 (IGF-1 and IGF-2) are well-known neuroprotectors, and IGF concentration elevation might be an adaptive cell reaction activated in response to the developing pathology in the brain, as well as senescence. In the present study, using a primary astrocyte culture isolated from neonatal rats of different age and the model of astrocyte senescence induction by low doses of etoposide, we demonstrated the activation of mechanism that increase IGF concentration in the brain during aging—the proteolytic cleavage of IGFBP-4 protein (Insulin-like Growth Factor Binding Protein-4) under the action of PAPP-A (Pregnancy Associated Plasma Protein A) protease. The results of the study suggest that this mechanism may be important in providing neuroprotection of cells in the early stages of cell aging.