Dataset Information

Interleukin-1? mediates alterations in mitochondrial fusion/fission proteins and memory impairment induced by amyloid-? 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-? oligomers (A?Os) and carried out A?O infusions into the lateral cerebral ventricle of cynomolgus macaques to assess the impact of A?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?Os in the presence or absence of mdivi-1. To assess the role of interleukin-1 beta (IL-1?) in A?O-induced alterations in mitochondrial proteins and memory impairment, interleukin receptor-1 knockout (Il1r1^-/-) mice received an i.c.v. infusion of A?Os.

Results

We report that anakinra prevented A?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?Os. The mitochondrial fission inhibitor, mdivi-1, alleviated synapse loss and cognitive impairment induced by A?Os in mice. In addition, A?Os failed to cause alterations in expression of mitochondrial dynamics proteins or memory impairment in Il1r1^-/- mice.

Conclusion

These findings indicate that IL-1? mediates the impact of A?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.

SUBMITTER: Batista AF

PROVIDER: S-EPMC7897381 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Batista Andre F AF Rody Tayná T Forny-Germano Leticia L Cerdeiro Suzana S Bellio Maria M Ferreira Sergio T ST Munoz Douglas P DP De Felice Fernanda G FG

Journal of neuroinflammation 20210221 1

<h4>Background</h4>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- ...[more]

PMID: 33612100

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