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Related Experiment Video

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Tacrolimus Protects against Age-Associated Microstructural Changes in the Beagle Brain.

Hamsanandini Radhakrishnan1, Margo F Ubele2, Stephanie M Krumholz2

  • 1Mathematical, Computational and Systems Biology, University of California, Irvine, Irvine, California 92697.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|May 6, 2021
PubMed
Summary

Tacrolimus, a calcineurin inhibitor, prevents age-related brain changes like inflammation and microstructural atrophy in middle-aged beagles. This suggests potential for preventing Alzheimer

Keywords:
Alzheimer's diseaseagingcalcineurincaninediffusion-weighted imagingneuroinflammation

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Aging Research

Background:

  • Calcineurin overexpression is linked to astrocyte hyperactivation, neuronal death, and neuroinflammation, hallmarks of pathologic aging and Alzheimer's disease (AD).
  • Early intervention targeting calcineurin signaling may offer a strategy to prevent age- and AD-associated neurodegeneration before significant cognitive decline.

Purpose of the Study:

  • To investigate whether tacrolimus, a calcineurin inhibitor, can prevent age-associated microstructural brain atrophy in middle-aged beagles.
  • To assess the impact of tacrolimus on specific brain regions, including the hippocampus, parahippocampal cortex, and prefrontal cortex.

Main Methods:

  • Administration of tacrolimus to middle-aged beagles (n=30) over one year.
  • Utilized higher-order diffusion magnetic resonance imaging (dMRI) to measure microstructural changes.
  • Quantified key dMRI metrics such as neurite density index, orientation dispersion index, and fractional anisotropy.

Main Results:

  • Tacrolimus significantly reduced neurite density index in the hippocampus and parahippocampal cortex.
  • Tacrolimus protected against age-associated increases in the parahippocampal orientation dispersion index.
  • Tacrolimus prevented age-related decreases in fractional anisotropy in the prefrontal cortex, with no observed adverse effects.

Conclusions:

  • Calcineurin inhibition with tacrolimus effectively preserves brain microstructural integrity and prevents age-related changes in middle-aged beagles.
  • These findings suggest that calcineurin inhibitors could be a promising therapeutic strategy for preventing aging-related brain pathology and Alzheimer's disease if administered proactively.
  • The observed microstructural improvements precede gross atrophy and cognitive decline, highlighting the potential for early intervention.