Ethanol Alters APP Processing and Aggravates Alzheimer-Associated Phenotypes
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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.
KeywordsEthanol exposure Alzheimer’s disease APP processing BACE1 Aβ Cognitive deficits
Amyloid β precursor protein
Beta-site APP cleaving enzyme 1
Amyloid β protein
Drinking in the dark
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.
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.
Compliance with Ethical Standards
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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