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

Abstract

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-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. Results We 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. Conclusion These 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.

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“…Additionally, mitochondrial trafficking within the cell—for example, for cell membrane repair [ 46 ]—depends on fission. Alterations of mitochondrial dynamics are suspected to be involved in the neurodegenerative process and have been demonstrated in models for all major neurodegenerative diseases, including AD [ 47 ] and PD [ 48 ]. Missense mutations in proteins involved in mitochondrial dynamics, furthermore, are associated with parkinsonism and dementias, such as AD [ 49 ].…”

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“…Mitochondrial fission often results in dysfunctional and fragmented mitochondria and the balance between fission and fusion is regulated by fusion proteins, including mitofusin 1 (Mfn1) and 2 (Mfn2), and optic atrophy 1 (OPA-1), and fission proteins, such as dynamin-1-like protein (DRP-1) and mitochondrial fission 1 protein (Fis1). In cynomolgus macaques, the expression of mitochondrial fusion proteins (Mfn1, Mfn2, and OPA-1) was reduced and the fission protein DRP-1 was increased after ventricular infusion of oligomeric Aβ, indicating disruption of mitochondrial dynamics and induction of fission [ 178 ]. We have recently shown that Ca 2+ -induced mPTP opening in vitro enhances proteolytic cleavage of L-OPA1 leading to accumulation of S-OPA1 [ 179 ], indicating a crosstalk between mPTP opening and mitochondrial dynamics.…”

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