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Chronic fornix deep brain stimulation in a transgenic Alzheimer’s rat model reduces amyloid burden, inflammation, and neuronal loss

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Abstract

Recent studies have suggested deep brain stimulation (DBS) as a promising therapy in patients with Alzheimer’s disease (AD). Particularly, the stimulation of the forniceal area was found to slow down the cognitive decline of some AD patients, but the biochemical and anatomical modifications underlying these effects remain poorly understood. We evaluated the effects of chronic forniceal stimulation on amyloid burden, inflammation, and neuronal loss in a transgenic Alzheimer rat model TgF344-AD, as well as in age-matched control rats. 18-month-old rats were surgically implanted with electrodes in stereotactic conditions and connected to a portable microstimulator for chronic DBS in freely moving rats. The stimulation was continuous during 5 weeks and animals were immediately sacrificed for immunohistochemical analysis of pathological markers. Implanted, but non-stimulated rats were used as controls. We found that chronic forniceal DBS in the Tg-AD rat significantly reduces amyloid deposition in the hippocampus and cortex, decreases astrogliosis and microglial activation and lowers neuronal loss, as determined by NeuN staining. In control animals, the stimulation neither affects neuroinflammation nor neuronal count. In the Tg-F344-AD rat model, 5 weeks of forniceal DBS decreased amyloidosis, inflammatory responses, and neuronal loss in both cortex and hippocampus. These findings strongly suggest a neuroprotective effect of DBS and support the beneficial effects of targeting the fornix in Alzheimer’s disease patients.

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Acknowledgements

We wish to thank Dr. T. Town for providing access to the rats. This work has been developed and supported through the LABEX (excellence laboratory, program investment for the future) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s) disease and the Hospital University Federation (FHU) OncoAge. We would like to warmly thank the anonymous donor who contributed significantly with several gifts to our study. This study has been supported by the “Harmonie Alzheimer” award (Fondation de l’Avenir, Harmonie Mutuelle), the “Société Francaise de Neurochirurgie” award and St Jude-Abott.

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Author notes

  1. Denys Fontaine and Frederic Checler contributed equally to this study.

Authors and Affiliations

  1. Departement of Neurosurgery, Université Nice Côte d’Azur, Centre Hospitalier Universitaire de Nice, Nice, France

    Aurelie Leplus & Denys Fontaine

  2. Université Côte d’Azur, INSERM, CNRS/UMR7275, IPMC, Team Labeled “Laboratory of Excellence (LABEX) Distalz”, 660 route des Lucioles, 06560, Sophia-Antipolis, Valbonne, France

    Aurelie Leplus, Inger Lauritzen & Frederic Checler

  3. Aix-Marseille University, IBDML, 13288, Marseille Cx 9, France

    Christophe Melon & Lydia Kerkerian-Le Goff

  4. CNRS, UMR 7288, IBDML, 13288, Marseille Cx 9, France

    Christophe Melon & Lydia Kerkerian-Le Goff

Authors
  1. Aurelie Leplus
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  2. Inger Lauritzen
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  3. Christophe Melon
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  4. Lydia Kerkerian-Le Goff
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  5. Denys Fontaine
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  6. Frederic Checler
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Corresponding author

Correspondence to Aurelie Leplus.

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The authors declare that they have no conflict of interest.

Ethical standards

All applicable European guidelines for the care and use of animals were followed. This study was approved by the Institute Animal Care Committee. All experiments are in accordance with the European Communities Council Directive of November 24, 1986 (86/609/EEC).

Studies involving human and animal participants

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Leplus, A., Lauritzen, I., Melon, C. et al. Chronic fornix deep brain stimulation in a transgenic Alzheimer’s rat model reduces amyloid burden, inflammation, and neuronal loss. Brain Struct Funct 224, 363–372 (2019). https://doi.org/10.1007/s00429-018-1779-x

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  • DOI: https://doi.org/10.1007/s00429-018-1779-x

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