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Brain Structure and Function

, Volume 223, Issue 7, pp 3365–3382 | Cite as

Early-in-life neuroanatomical and behavioural trajectories in a triple transgenic model of Alzheimer’s disease

  • Vincent Kong
  • Gabriel A. Devenyi
  • Daniel Gallino
  • Gülebru Ayranci
  • Jürgen Germann
  • Colleen Rollins
  • M. Mallar Chakravarty
Original Article

Abstract

Animal models of Alzheimer’s disease (AD) can be used to determine the progressive neurodegeneration characteristics of AD in vivo using magnetic resonance imaging (MRI). Given the need for therapeutic interventions before the onset of frank AD, it is critical to examine if AD models demonstrate neuroanatomical remodeling in an equivalent preclinical phase. This manuscript examines the trajectories of brain and behavioural changes in the Triple transgenic mouse model (3xTg) prior to the development of AD-like behaviours. The 3xTg mimics both β-amyloid plaques and neurofibrillary tangles through three mutations associated with familial AD, namely: PS1M146V, APPSwe, and tauP301L transgenes. We performed detailed investigation using longitudinal structural MRI at 6, 8, 12, 16, 20, and 24 weeks old to assess neuroanatomical changes using volumetric and deformation-based analyses. Learning- and memory-related behaviour were assessed through the Morris water maze at 9, 17, and 25 weeks of age. There was the absence of major memory deficits with the notable exception of water maze conducted at 17 weeks old, where 3xTg group spent significantly less time in the quadrant of interest in the probe trial. Through volumetric and deformation-based analyses, we observed relative decrease over time in the 3xTg group in the third ventricle, piriform cortex, fornix, and fimbria relative to the control group. We also observed decreases over time in the control mice in the hippocampus, entorhinal cortex, cerebellum, and olfactory bulb. In many of these cases, we note a delay in the attainment of peak volume in the 3xTgs relative to the control group, suggesting a possible neurodevelopmental and maturational delay given the likely over-expression of AD-related pathology from birth. Importantly, neuroanatomical alterations are observed prior to the manifestation of AD-like behaviours, suggesting that mutated amyloid and tau are, indeed, sufficient to cause changes in the neuroanatomy in 3xTg mice, but potentially insufficient to be responsible for behavioural changes in the earlier stages of life.

Keywords

Magnetic resonance imaging Alzheimer’s disease Behaviour Longitudinal Phenotyping 

Notes

Acknowledgements

MMC receives research support from the Canadian Institutes of Health Research, National Sciences and Research Council of Canada, Weston Brain Institute, and Brain Canada. MMC also receives salary support from Fonds de Recherche Santé Québec.

Supplementary material

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Supplementary Material 1. (CSV 49 kb)
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Supplementary Material 2. (CSV 42 kb)
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Supplementary Material 3. (CSV 55 kb)
429_2018_1691_MOESM4_ESM.docx (3.7 mb)
Supplementary Material 4. (DOCX 3,760 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Vincent Kong
    • 1
    • 2
  • Gabriel A. Devenyi
    • 1
    • 3
  • Daniel Gallino
    • 1
  • Gülebru Ayranci
    • 1
  • Jürgen Germann
    • 1
  • Colleen Rollins
    • 1
  • M. Mallar Chakravarty
    • 1
    • 2
    • 3
    • 4
  1. 1.Computational Brain Anatomy Laboratory (CoBrA Lab), Cerebral Imaging CentreDouglas Mental Health University InstituteMontrealCanada
  2. 2.Integrated Program in NeuroscienceMcGill UniversityMontrealCanada
  3. 3.Department of PsychiatryMcGill UniversityMontrealCanada
  4. 4.Department of Biological and Biomedical EngineeringMcGill UniversityMontrealCanada

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