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

Journal of Neuroinflammation

Douglas P. Munoz¹  Maria Bellio²  Andre F. Batista³  Leticia Forny-Germano³  Suzana Cerdeiro³  Tayná Rody³  Fernanda G. De Felice⁴  Sergio T. Ferreira⁵ 

[1]Centre for Neuroscience Studies, Queen’s University, K7L3N6, Kingston, Ontario, Canada

[2]Department of Immunology, Institute of Microbiology Paulo de Góes, Federal University of Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil

[3]Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, CCS, room H2-019, 21941-590, Rio de Janeiro, RJ, Brazil

[4]Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, CCS, room H2-019, 21941-590, Rio de Janeiro, RJ, Brazil

[5]Centre for Neuroscience Studies, Queen’s University, K7L3N6, Kingston, Ontario, Canada

[6]Department of Psychiatry, Queen’s University, K7L3N6, Kingston, Ontario, Canada

[7]Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, CCS, room H2-019, 21941-590, Rio de Janeiro, RJ, Brazil

[8]Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil

关键词: Alzheimer’s disease;    Mitochondrial dynamics;    Mitochondrial dysfunction;    IL-1β;    Neuroinflammation;    Aβ oligomers;   

DOI  :  10.1186/s12974-021-02099-x

来源: Springer

【 摘 要 】

BackgroundThe 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.MethodsWe exposed primary hippocampal cell cultures to amyloid-β oligomers (AβOs) and carried out AβO infusions into the lateral cerebral ventricle of cynomolgus macaques to assess the impact of AβOs 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 AβOs in the presence or absence of mdivi-1. To assess the role of interleukin-1 beta (IL-1β) in AβO-induced alterations in mitochondrial proteins and memory impairment, interleukin receptor-1 knockout (Il1r1−/−) mice received an i.c.v. infusion of AβOs.ResultsWe report that anakinra prevented AβO-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 AβOs. The mitochondrial fission inhibitor, mdivi-1, alleviated synapse loss and cognitive impairment induced by AβOs in mice. In addition, AβOs failed to cause alterations in expression of mitochondrial dynamics proteins or memory impairment in Il1r1−/− mice.ConclusionThese findings indicate that IL-1β mediates the impact of AβOs 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.

【 授权许可】

CC BY