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Effects of sub-chronic donepezil on brain Abeta and cognition in a mouse model of Alzheimer’s disease

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Abstract

Rationale

Acetylcholinesterase inhibitors (AChEIs) are approved to treat the symptoms of mild to moderate Alzheimer’s disease by restoring acetylcholine levels at synapses where the neurotransmitter has been depleted due to neurodegeneration. This assumption is challenged by more recent clinical studies suggesting the potential for disease-modifying effects of AChEIs as well as in vitro studies showing neuroprotective effects. However, few preclinical studies have assessed whether the improvement of cognitive symptoms may be mediated by reductions in Abeta or Tau pathology.

Objectives

The objective of the present study was to determine whether short-duration treatment with donepezil could improve spatial learning and memory in transgenic mice overexpressing mutant human amyloid precursor protein (hAPP) and presenilin 1 (PS1) (Dewachter et al., J Neurosci 20(17):6452–6458, 2000) after amyloid pathology has fully developed, consistent with early stages of Alzheimer’sdisease in humans. In parallel, the effect of donepezil treatment on brain amyloid, Tau, and glial endpoints was measured.

Results

This study showed a significant improvement in reference memory in hAPP/PS1 mice along with dose-dependent reductions in brain amyloid-β (Aβ).

Conclusion

These results suggest that the observed cognitive improvement produced by donepezil in Alzheimer’s disease may be due, at least in part, to reduction of brain Aβ.

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Acknowledgements

Thank you to Cathy Kieras and Ivar McDonald.

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Authors and Affiliations

  1. Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT, 06492, USA

    Amy Easton, Sethu Sankaranarayanan, An Tanghe, Dick Terwel, Alan X. Lin, Nina Hoque, Clotilde Bourin, Huidong Gu, Michael Ahlijanian & Linda Bristow

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  1. Amy Easton
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  2. Sethu Sankaranarayanan
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  3. An Tanghe
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Correspondence to Amy Easton.

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Easton, A., Sankaranarayanan, S., Tanghe, A. et al. Effects of sub-chronic donepezil on brain Abeta and cognition in a mouse model of Alzheimer’s disease. Psychopharmacology 230, 279–289 (2013). https://doi.org/10.1007/s00213-013-3152-3

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