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Early manifestation of gait alterations in the Tg2576 mouse model of Alzheimer’s disease

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Abstract

There is strong clinical evidence that multifaceted gait abnormalities may be manifested at early stages of Alzheimer’s disease (AD), are related to cognitive decline, and can be used as an early biomarker to identify patients at risk of progressing to full-blown dementia. Despite their importance, gait abnormalities have not been investigated in mouse models of AD, which replicate important aspects of the human disease. The Tg2576 is frequently used in AD research to test therapeutic interventions targeting cellular mechanisms contributing to the genesis of AD. This transgenic mouse strain overexpresses a mutant form of the 695 amino acid isoform of human amyloid precursor protein with K670N and M671L mutations (APPK670/671L) linked to early-onset familial AD. Tg2576 mice exhibit impaired cognitive functions and increased cortical and hippocampal soluble β-amyloid levels starting from 5 months of age and increased insoluble β-amyloid levels and amyloid plaques that resemble senile plaques associated with human AD by 13 months of age. To demonstrate early manifestations of gait dysfunction in this relevant preclinical model, we characterized gait and motor performance in 10-month-old Tg2576 mice and age-matched littermate controls using the semi-automated, highly sensitive, Catwalk XT system. We found that Tg2576 mice at the pre-plaque stage exhibited significantly altered duty cycle and step patterns and decreased stride length and stride time. Base-of-support, stride time variability, stride length variability, cadence, phase dispersions and gait symmetry indices were unaltered. The presence of measurable early gait abnormalities during the pre-plaque stages of AD in this relevant preclinical mouse model has direct translational relevance and supports the view that longitudinal monitoring of gait performance could be used in addition to behavioral testing to evaluate progression of the disease and to assess treatment efficacy.

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Acknowledgements

This work was supported by grants from the American Heart Association, the Oklahoma Center for the Advancement of Science and Technology, the National Institute on Aging ((R01-AG055395, R01-AG047879; R01-AG038747; R01-AG072295), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS100782), the National Cancer Institute (NCI; 1R01CA255840), the Oklahoma Shared Clinical and Translational Resources (OSCTR) program funded by the National Institute of General Medical Sciences (U54GM104938, to AY), the Presbyterian Health Foundation and the NKFIH (Nemzeti Szivlabor). The authors acknowledge the support from the NIA-funded Geroscience Training Program in Oklahoma (T32AG052363), the Oklahoma Nathan Shock Center (P30AG050911), the Cellular and Molecular GeroScience CoBRE (1P20GM125528, sub#5337). The funding sources had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

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  1. Anna Csiszar, Zoltan Ungvari, and Stefano Tarantini contributed equally to this work.

Authors and Affiliations

  1. Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience and Healthy Brain Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 975 N. E. 10th Street - BRC 1303, Oklahoma City, OK, 73104, USA

    Adam Nyul-Toth, Jordan DelFavero, Peter Mukli, Amber Tarantini, Anna Ungvari, Andriy Yabluchanskiy, Anna Csiszar, Zoltan Ungvari & Stefano Tarantini

  2. International Training Program in Geroscience, Institute of Biophysics, Biological Research Centre, Eötvös Loránd Research Network (ELKH), Szeged, Hungary

    Adam Nyul-Toth

  3. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Physiology, Semmelweis University, Budapest, Hungary

    Peter Mukli

  4. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Translational Medicine, Semmelweis University, Budapest, Hungary

    Anna Csiszar

  5. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary

    Zoltan Ungvari & Stefano Tarantini

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  1. Adam Nyul-Toth
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Correspondence to Zoltan Ungvari or Stefano Tarantini.

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Dr. Anna Csiszar serves as Associate Editor for The Journal of Gerontology, Series A: Biological Sciences and Medical Sciences and GeroScience. Dr. Andriy Yabluchanskiy serves as Guest Editor for The American Journal of Physiology-Heart and Circulatory Physiology. Dr. Zoltan Ungvari serves as Editor-in-Chief for GeroScience and as Consulting Editor for The American Journal of Physiology-Heart and Circulatory Physiology. The authors declare no competing financial interests.

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Nyul-Toth, A., DelFavero, J., Mukli, P. et al. Early manifestation of gait alterations in the Tg2576 mouse model of Alzheimer’s disease. GeroScience 43, 1947–1957 (2021). https://doi.org/10.1007/s11357-021-00401-6

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