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Ethanol Alters APP Processing and Aggravates Alzheimer-Associated Phenotypes

Molecular Neurobiology volume 55, pages 5006–5018 (2018)Cite this article

Abstract

The majority of Alzheimer’s disease (AD) cases are sporadic with unknown causes. Many dietary factors including excessive alcohol intake have been reported to increase the risk to develop AD. The effect of alcohol on cognitive functions and AD pathogenesis remains elusive. In this study, we investigated the relationship between ethanol exposure and Alzheimer’s disease. Cell cultures were treated with ethanol at different dosages for different durations up to 48 h and an AD model mouse was fed with ethanol for 4 weeks. We found that ethanol treatment altered amyloid β precursor protein (APP) processing in cells and transgenic AD model mice. High ethanol exposure increased the levels of APP and beta-site APP cleaving enzyme 1 (BACE1) and significantly promoted amyloid β protein (Aβ) production both in vitro and in vivo. The upregulated APP and BACE1 expressions upon ethanol treatment were at least partially due to the activation of APP and BACE1 transcriptions. Furthermore, ethanol treatment increased the deposition of Aβ and neuritic plaque formation in the brains and exuberated learning and memory impairments in transgenic AD model mice. Taken together, our results demonstrate that excessive ethanol intake facilitates AD pathogenesis.

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Abbreviations

AD:

Alzheimer’s disease

APP:

Amyloid β precursor protein

BACE1:

Beta-site APP cleaving enzyme 1

Aβ:

Amyloid β protein

DID:

Drinking in the dark

CHX:

Cycloheximide

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Acknowledgements

We sincerely thank Philip T.T. Ly, Zhifang Dong, and Mingjing Liu for their helpful comments. This work was supported by grants from the National Natural Science Foundation of China (NSFC) Grant 30972461, 81161120498 (T.L.) and the Canadian Institutes of Health Research (CIHR) Grant TAD-117948 (W.S). W.S. is the holder of the Tier 1 Canada Research Chair in Alzheimer’s Disease.

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Authors and Affiliations

  1. Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, China

    Daochao Huang, Mengjiao Yu, Shou Yang, Dandan Lou, Weitao Zhou, Lingling Zheng, Weihui Zhou, Tingyu Li & Weihong Song

  2. Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada

    Zhe Wang, Fang Cai & Weihong Song

Authors
  1. Daochao Huang
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  2. Mengjiao Yu
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  3. Shou Yang
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  4. Dandan Lou
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  5. Weitao Zhou
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  7. Zhe Wang
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  8. Fang Cai
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  9. Weihui Zhou
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  10. Tingyu Li
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  11. Weihong Song
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Contributions

DH and WS conceived and designed the experiments; DH, MY, SY, DL, WZ, LZ, and FC performed the experiments; DH, MY, SY, DL, WZ, LZ, ZW, WZ, TL, and WS analyzed and contributed reagents/materials/analysis tools; and DH, ZW, and WS wrote the paper. All authors reviewed the manuscript.

Corresponding author

Correspondence to Weihong Song.

Ethics declarations

All animal studies were performed in accordance with the Guide for the Care and Use of Laboratory Animals of the Ethics Committee of Chongqing Medical University. The experimental protocols were approved by the Animal Study Committee of the Children’s Hospital of Chongqing Medical University.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Huang, D., Yu, M., Yang, S. et al. Ethanol Alters APP Processing and Aggravates Alzheimer-Associated Phenotypes. Mol Neurobiol 55, 5006–5018 (2018). https://doi.org/10.1007/s12035-017-0703-3

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