Interleukin-1β mediates alterations in mitochondrial fusion/fission proteins and memory impairment induced by amyloid-β oligomers

Background The lack of effective treatments for Alzheimer's disease (AD) reflects an incomplete understanding of disease mechanisms. Alterations in proteins involved in mitochondrial dynamics, an essential process for mitochondrial integrity and function, have been reported in AD brains. Impaired mitochondrial dynamics causes mitochondrial dysfunction and has been associated with cognitive impairment in AD. Here, we investigated a possible link between pro-inflammatory interleukin-1 (IL-1), mitochondrial dysfunction, and cognitive impairment in AD models. Methods We exposed primary hippocampal cell cultures to amyloid-beta oligomers (A beta Os) and carried out A beta O infusions into the lateral cerebral ventricle of cynomolgus macaques to assess the impact of A beta Os on proteins that regulate mitochondrial dynamics. Where indicated, primary cultures were pre-treated with mitochondrial division inhibitor 1 (mdivi-1), or with anakinra, a recombinant interleukin-1 receptor (IL-1R) antagonist used in the treatment of rheumatoid arthritis. Cognitive impairment was investigated in C57BL/6 mice that received an intracerebroventricular (i.c.v.) infusion of A beta Os in the presence or absence of mdivi-1. To assess the role of interleukin-1 beta (IL-1 beta) in A beta O-induced alterations in mitochondrial proteins and memory impairment, interleukin receptor-1 knockout (Il1r1(-/-)) mice received an i.c.v. infusion of A beta Os. Results We report that anakinra prevented A beta O-induced alteration in mitochondrial dynamics proteins in primary hippocampal cultures. Altered levels of proteins involved in mitochondrial fusion and fission were observed in the brains of cynomolgus macaques that received i.c.v. infusions of A beta Os. The mitochondrial fission inhibitor, mdivi-1, alleviated synapse loss and cognitive impairment induced by A beta Os in mice. In addition, A beta Os failed to cause alterations in expression of mitochondrial dynamics proteins or memory impairment in Il1r1(-/-) mice. Conclusion These findings indicate that IL-1 beta mediates the impact of A beta Os on proteins involved in mitochondrial dynamics and that strategies aimed to prevent pathological alterations in those proteins may counteract synapse loss and cognitive impairment in AD.

Automated summary

The study found that IL-1 beta mediates the impact of A beta Os on proteins involved in mitochondrial dynamics, and suggests that strategies aimed at preventing pathological alterations in these proteins may counteract synapse loss and cognitive impairment in Alzheimer's disease (AD).