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Progressive Pathological Changes in Neurochemical Profile of the Hippocampus and Early Changes in the Olfactory Bulbs of Tau Transgenic Mice (rTg4510)

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Abstract

Tauopathies such as Alzheimer’s disease and frontotemporal lobe degeneration (FTLD-tau) dementia, characterized by pathologic aggregation of the microtubule-associated tau protein and formation of neurofibrillary tangles, have been linked to neurodegeneration and cognitive decline. The early detection of cerebral abnormalities and the identification of biological contributors to the continuous pathologic processes of neurodegeneration in tauopathies critically hinge on sensitive and reliable measures of biomarkers in the living brain. In this study, we measured alterations in a number of key neurochemicals associated with tauopathy-induced neurodegeneration in the hippocampus and the olfactory bulbs of a transgenic mouse model of FTLD-tauopathy, line rTg4510, using in vivo 1H magnetic resonance spectroscopy at 9.4 T. The rTg4510 line develops tauopathy at a young age (4–5 months), reaching a severe stage by 8–12 months of age. Longitudinal measurement of neurochemical concentrations in the hippocampus of mice from 5 to 12 months of age showed significant progressive changes with distinctive disease staging patterns including N-acetylaspartate, myo-inositol, γ-aminobutyric acid, glutathione and glutamine. The accompanying hippocampal volume loss measured using magnetic resonance imaging showed significant correlation (p < 0.01) with neurochemical measurements. Neurochemical alterations in the olfactory bulbs were more pronounced than those in the hippocampus in rTg4510 mice. These results demonstrate progressive neuropathology in the mouse model and provide potential biomarkers of early neuropathological events and effective noninvasive monitoring of the disease progression and treatment efficacy, which can be easily translated to clinical studies.

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Acknowledgements

This study was supported in part by Alzheimer’s Association (NIRG-07-60405 to Dr. Lee). Hoglund Brain Imaging Center is supported by the Hoglund Family Foundation and NIH (P30 HD002528).

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Authors and Affiliations

  1. Hoglund Brain Imaging Center, University of Kansas Medical Center, 3901 Rainbow Blvd, Mail Stop 1052, Kansas City, KS, 66160, USA

    Jieun Kim, In-Young Choi & Phil Lee

  2. Department of Neurology, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    In-Young Choi

  3. Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    In-Young Choi & Phil Lee

  4. Department of Integrative Neuroscience, Columbia University Medical Center, New York, NY, 10032, USA

    Karen E. Duff

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  1. Jieun Kim
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Correspondence to Phil Lee.

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Kim, J., Choi, IY., Duff, K.E. et al. Progressive Pathological Changes in Neurochemical Profile of the Hippocampus and Early Changes in the Olfactory Bulbs of Tau Transgenic Mice (rTg4510). Neurochem Res 42, 1649–1660 (2017). https://doi.org/10.1007/s11064-017-2298-5

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  • DOI: https://doi.org/10.1007/s11064-017-2298-5

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