Abstract
Cognitive decline with age is a harmful process that can reduce quality of life. Multiple factors have been established to contribute to cognitive decline, but the overall etiology remains unknown. Here, we hypothesized that cognitive dysfunction is mediated, in part, by increased levels of inflammatory cytokines that alter allopregnanolone (AlloP) levels, an important neurosteroid in the brain. We assessed the levels and regulation of AlloP and the effects of AlloP supplementation on cognitive function in 4-month-old and 24-month-old male C57BL/6 mice. With age, the expression of enzymes involved in the AlloP synthetic pathway was decreased and corticosterone (CORT) synthesis increased. Supplementation of AlloP improved cognitive function. Interestingly, interleukin 6 (IL-6) infusion in young animals significantly reduced the production of AlloP compared with controls. It is notable that inhibition of IL-6 with its natural inhibitor, soluble membrane glycoprotein 130, significantly improved spatial memory in aged mice. These findings were supported by in vitro experiments in primary murine astrocyte cultures, indicating that IL-6 decreases production of AlloP and increases CORT levels. Our results indicate that age-related increases in IL-6 levels reduce progesterone substrate availability, resulting in a decline in AlloP levels and an increase in CORT. Furthermore, our results indicate that AlloP is a critical link between inflammatory cytokines and the age-related decline in cognitive function.
Highlights
Previous studies have clearly indicated that aging is the primary risk factor for cognitive decline and neurodegenerative disease [1,2,3]
We investigated the effects of AlloP on cognitive function in aged (24 months) mice as well as the impact of interleukin 6 (IL-6) on AlloP synthesis
AlloP levels are altered with age AlloP is synthesized from PRG via two enzymatic steps
Summary
Previous studies have clearly indicated that aging is the primary risk factor for cognitive decline and neurodegenerative disease [1,2,3]. Previous studies indicate that interleukin 6 (IL-6), an inflammatory cytokine, increases with age and, in the adrenal cortex, upregulates the expression of two enzymes, 11 hydroxylase and 21-hydroxylase, which convert PRG to CORT [10]. These enzymes, as well as others that lead to AlloP synthesis, are found in the endoplasmic reticulum and are expressed throughout various cell types in the brain [11]. Our data show that the expression and activity of PRG-metabolizing enzymes change with age, likely contributing to the reduced production of AlloP
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