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Prolonged Running, not Fluoxetine Treatment, Increases Neurogenesis, but does not Alter Neuropathology, in the 3xTg Mouse Model of Alzheimer’s Disease

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Neurogenesis and Neural Plasticity

Part of the book series: Current Topics in Behavioral Neurosciences ((CTBN,volume 15))

Abstract

Reductions in adult neurogenesis have been documented in the original 3xTg mouse model of Alzheimer’s disease (AD), notably occurring at the same age when spatial memory deficits and amyloid plaque pathology appeared. As this suggested reduced neurogenesis was associated with behavioral deficits, we tested whether activity and pharmacological stimulation could prevent memory deficits and modify neurogenesis and/or neuropathology in the 3xTg model backcrossed to the C57Bl/6 strain. We chronically administered the antidepressant fluoxetine to one group of mice, allowed access to a running wheel in another, and combined both treatments in a third cohort. All treatments lasted for 11 months. The female 3xTg mice failed to exhibit any deficits in spatial learning and memory as measured in the Morris water maze, indicating that when backcrossed to the C57Bl/6 strain, the 3xTg mice lost the behavioral phenotype that was present in the original 3xTg mouse maintained on a hybrid background. Despite this, the backcrossed 3xTg mice expressed prominent intraneuronal amyloid beta (Aβ) levels in the cortex and amygdala, with lower levels in the CA1 area of the hippocampus. In the combined cohort, fluoxetine treatment interfered with exercise and reduced the total distance run. The extent of Aβ neuropathology, the tau accumulations, or BDNF levels, were not altered by prolonged exercise. Thus, neuropathology was present but not paralleled by spatial memory deficits in the backcrossed 3xTg mouse model of AD. Prolonged exercise for 11 months did improve the long-term survival of newborn neurons generated during middle-age, whereas fluoxetine had no effect. We further review and discuss the relevant literature in this respect.

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Acknowledgments

This work was supported in part by the National Institute on Aging (NIA), Intramural Research Program. We thank Dr. Mark Mattson (NIA) for providing the 3xTg mice. MM, TAB, and PJL are supported by the EU (NEURAD consortium). MM and PJL are supported by ISAO. PJL is further supported by the Dutch Brain Foundation, by the International Parkinson Foundation IPF, and by the Netherlands Organization for Scientific Research NWO.

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Authors and Affiliations

  1. Swammerdam Institute for Life Science—Center for Neuroscience, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands

    Michael W. Marlatt & Paul J. Lucassen

  2. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA

    Michael W. Marlatt, Michelle C. Potter & Henriette van Praag

  3. Division of Molecular Psychiatry, Georg-August-Universität Goettingen, Goettingen, Germany

    Thomas A. Bayer

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  1. Michael W. Marlatt
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  2. Michelle C. Potter
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  3. Thomas A. Bayer
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  4. Henriette van Praag
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  5. Paul J. Lucassen
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Correspondence to Paul J. Lucassen .

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  1. , INSERM 930, Faculté des Sciences, Parc Grandmont, Tours, 37200, France

    Catherine Belzung

  2. Medical School, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2UH, United Kingdom

    Peter Wigmore

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Marlatt, M.W., Potter, M.C., Bayer, T.A., van Praag, H., Lucassen, P.J. (2013). Prolonged Running, not Fluoxetine Treatment, Increases Neurogenesis, but does not Alter Neuropathology, in the 3xTg Mouse Model of Alzheimer’s Disease. In: Belzung, C., Wigmore, P. (eds) Neurogenesis and Neural Plasticity. Current Topics in Behavioral Neurosciences, vol 15. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7854_2012_237

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