Interleukin 6 reduces allopregnanolone synthesis in the brain and contributes to age-related cognitive decline in mice

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 levels, an important neurosteroid in the brain. We assessed the levels and regulation of allopregnanolone and the effects of allopregnanolone 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 allopregnanolone synthetic pathway were decreased and corticosterone synthesis increased. Supplementation of allopregnanolone improved cognitive function. Interestingly, IL-6 infusion in young animals significantly reduced the production of allopregnanolone compared to controls. Of note, inhibition of IL-6 with its natural inhibitor, soluble membrane glycoprotein gp130 (sgp130), 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 allopregnanolone and increases corticosterone levels. Our results indicate that age-related increases in IL-6 levels reduce progesterone substrate availability, resulting in a decline in allopregnanolone levels and an increase in corticosterone. Furthermore, our results indicate that allopregnanolone is a critical link between inflammatory cytokines and the age-related decline in cognitive function.

Effect of Allopregnanolone on Spatial Memory and Synaptic Proteins in Animal Model of Metabolic Syndrome

“…Our results demonstrated the prominent therapeutic effect of Allopregnanolone on working spatial memory, evidenced by the significant improvement of alternation score in the Allopregnanolone group compared to the MetS group ( Figure 1 ). These results are concomitant with the study done by Park et al, [ 6 ], who assessed the effect of Allopregnanolone on spatial learning and memory in aged mice using the radial arm water maze. Additionally, Frye et al [ 44 ] demonstrated that Allopregnanolone administration improved T-maze and water maze task performance.…”

“…Neurosteroids are steroid hormones synthesized de novo in the brain and peripheral nervous tissues [ 5 ]. Allopregnanolone is an essential neurosteroid in the brain, synthesized locally or in the periphery, and reaches the brain by crossing the blood-brain barrier [ 6 ]. Allopregnanolone levels were reported to be downregulated in neurodegenerative diseases [ 7 ].…”

Measuring Behavior in the Home Cage: Study Design, Applications, Challenges, and Perspectives

“…Furthermore, the assessment of ''age-related cognitive impairment'' is a critical scientific research area in human disease. Recent evidence of cognitive impairment in a mouse model of accelerated aging using the PhenoTyper indicates the translational potential for assessing cognitive function in various models of aging and models designed to mitigate age-related changes in learning and memory (Logan et al, 2019;Parks et al, 2020). In addition, when standard measurements like the Cumulative Learning Index (Logan et al, 2019) are proved to be…”

Psychoneuroimmunology in the context of perinatal depression - Tools for improved clinical practice

“…Interestingly, allopregnanolone, a progesterone metabolite, can inhibit proinflammatory processes through modulating GABA receptors (Balan, Beattie, O'Buckley, Aurelian and Morrow, 2019), while IL-6 decreases allopregnanolone synthesis in the brain ( Parks et al., 2020 ). While estrogen deficiency has been suggested as a risk for depressive behavior in animal models ( Xu, Sheng, Tang, Lu and Ni, 2015 ), estrogen has also been shown to increase during acute stress in humans ( Pletzer, Poppelaars, Klackl and Jonas, 2021 ).…”