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Reboxetine Treatment Reduces Neuroinflammation and Neurodegeneration in the 5xFAD Mouse Model of Alzheimer’s Disease: Role of CCL2

  • Irene L. Gutiérrez
  • Marta González-Prieto
  • Javier R. Caso
  • Borja García-Bueno
  • Juan C. Leza
  • José L. M. MadrigalEmail author
Article

Abstract

The reduction of brain noradrenaline levels is associated to the initiation of Alzheimer’s disease and contributes to its progression. This seems to be due mainly to the anti-neuroinflammatory actions of noradrenaline. The analysis of noradrenaline effects on brain cells demonstrates that it also regulates the production of the chemokine CCL2. In the present study, we analyzed the effect of the selective noradrenaline reuptake inhibitor, reboxetine, on the inflammatory and neurodegenerative alterations present in 5xFAD mice, and how the genetic removal of CCL2 affects reboxetine actions. We observed that the removal of CCL2 reduced the memory impairments in 5xFAD mice as well as the neuroinflammatory response, the accumulation of amyloid beta plaques, and the degeneration of neurons in the brain cortex. The administration of reboxetine with osmotic pumps for 28 days also resulted in anti-inflammatory and neuroprotective changes in 5xFAD mice, even in the absence of CCL2. Yet, 6-month-old CCL2KO mice presented a significant degree of neuroinflammation and neuronal damage. These findings indicate that reboxetine treatment prevents the brain alterations caused by prolonged overproduction of amyloid beta, being these effects independent of CCL2, which is a mediator of the damage caused by amyloid beta in the brain cortex, but necessary for the prevention of the development of neurodegeneration in normal healthy conditions.

Keywords

Noradrenaline Reboxetine CCL2 MCP-1 5xFAD Neuroinflammation 

Notes

Funding Information

This work was supported by the UCM (PR26/16-20278), the Spanish Ministry of Science (SAF2017-86620-R), and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM). ILG was supported by a Fellowship from the Spanish Ministry of Science. MGP was supported by a Fellowship from the European Youth Employment Initiative (YEI). BGB and JRC are Ramón y Cajal fellows (Spanish Ministry of Science).

Compliance with Ethical Standards

All experimental protocols adhered to the guidelines of the Animal Welfare Committee of the Universidad Complutense of Madrid, Spain (PROEX 052/17), and according to European Union laws (2010/63/EU).

Conflict of Interest

The authors declare that they have no conflict of interest.

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacology and Toxicology, School of MedicineUniversidad Complutense de Madrid (UCM)MadridSpain
  2. 2.Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)Instituto de Investigación Neuroquímica (IUINQ-UCM) and Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12)MadridSpain

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