Capsaicin consumption reduces brain amyloid-beta generation and attenuates Alzheimer’s disease-type pathology and cognitive deficits in APP/PS1 mice

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Abstract

Alzheimer’s disease (AD) is the most common cause of age-related dementia and is currently incurable. The failures of current clinical trials and the establishment of modifiable risk factors have shifted the AD intervention from treatment to prevention in the at-risk population. Previous studies suggest that there is a geographic overlap between AD incidence and spicy food consumption. We previously reported that capsaicin-rich diet consumption was associated with better cognition and lower serum Amyloid-beta (Aβ) levels in people aged 40 years and over. In the present study, we found that intake of capsaicin, the pungent ingredient in chili peppers, reduced brain Aβ burden and rescued cognitive decline in APP/PS1 mice. Our in vivo and in vitro studies revealed that capsaicin shifted Amyloid precursor protein (APP) processing towards α-cleavage and precluded Aβ generation by promoting the maturation of a disintegrin and metalloproteinase 10 (ADAM10). We also found that capsaicin alleviated other AD-type pathologies, such as tau hyperphosphorylation, neuroinflammation and neurodegeneration. The present study suggests that capsaicin is a potential therapeutic candidate for AD and warrants clinical trials on chili peppers or capsaicin as dietary supplementation for the prevention and treatment of AD.

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Most cited references 43

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As the field begins to test the concept of a "preclinical" stage of neurodegenerative disease, when the pathophysiological process has begun in the brain, but clinical symptoms are not yet manifest, a number of intriguing questions have already arisen. In particular, in preclinical Alzheimer's disease (AD), the temporal relationship of amyloid markers to markers of neurodegeneration and their relative utility in the prediction of cognitive decline among clinically normal older individuals remains to be fully elucidated. Secondary prevention trials in AD have already begun in both genetic at-risk and amyloid at-risk cohorts, with several more trials in the planning stages, and should provide critical answers about whether intervention at this very early stage of disease can truly bend the curve of clinical progression. This review will highlight recent progress in cognitive, imaging, and biomarker outcomes in the field of preclinical AD, and the remaining gaps in knowledge.

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Alzheimer disease (AD) is characterized by excessive deposition of amyloid beta-peptides (A beta peptides) in the brain. In the nonamyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by the alpha-secretase within the A beta peptide sequence. Proteinases of the ADAM family (adisintegrin and metalloproteinase) are the main candidates as physiologically relevant alpha-secretases, but early lethality of knockout animals prevented a detailed analysis in neuronal cells. To overcome this restriction, we have generated transgenic mice that overexpress either ADAM10 or a catalytically inactive ADAM10 mutant. In this report we show that a moderate neuronal overexpression of ADAM10 in mice transgenic for human APP([V717I]) increased the secretion of the neurotrophic soluble alpha-secretase-released N-terminal APP domain (APPs alpha), reduced the formation of A beta peptides, and prevented their deposition in plaques. Functionally, impaired long-term potentiation and cognitive deficits were alleviated. Expression of mutant catalytically inactive ADAM10 led to an enhancement of the number and size of amyloid plaques in the brains of double-transgenic mice. The results provide the first in vivo evidence for a proteinase of the ADAM family as an alpha-secretase of APP, reveal activation of ADAM10 as a promising therapeutic target, and support the hypothesis that a decrease in alpha-secretase activity contributes to the development of AD.

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Author and article information

Contributors

Jun Wang: qywangjun@163.com

Yan-Jiang Wang:

ORCID: http://orcid.org/0000-0002-6227-6112

yanjiang_wang@tmmu.edu.cn

Journal

Journal ID (nlm-ta): Transl Psychiatry

Journal ID (iso-abbrev): Transl Psychiatry

Title: Translational Psychiatry

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2158-3188

Publication date (Electronic): 13 July 2020

Publication date PMC-release: 13 July 2020

Publication date Collection: 2020

Volume: 10

Electronic Location Identifier: 230

Affiliations

[1 ]GRID grid.410570.7, ISNI 0000 0004 1760 6682, Department of Neurology and Center for Clinical Neuroscience, , Daping Hospital, Third Military Medical University, ; 400042 Chongqing, China

[2 ]GRID grid.410646.1, ISNI 0000 0004 1808 0950, Department of Neurology, , Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, ; 610072 Chengdu, China

[3 ]GRID grid.410570.7, ISNI 0000 0004 1760 6682, Shigatse Branch, Xinqiao Hospital, , Third Military Medical University, ; 857000 Shigatse, China

[4 ]GRID grid.410570.7, ISNI 0000 0004 1760 6682, Department of anaesthesiology, , Daping Hospital, Third Military Medical University, ; 400042 Chongqing, China

[5 ]Department of Neurology, Qingdao Municipal Hospital, Qingdao University, 266071 Qingdao, China

[6 ]GRID grid.410570.7, ISNI 0000 0004 1760 6682, Brain Research Center, , Third Military Medical University, ; 400038 Chongqing, China

[7 ]GRID grid.410570.7, ISNI 0000 0004 1760 6682, Department of Physiology and Institute of Brain and Intelligence, , Third Military Medical University, ; 400038 Chongqing, China

[8 ]GRID grid.410570.7, ISNI 0000 0004 1760 6682, Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, , Third Military Medical University, ; 400042 Chongqing, China

[9 ]GRID grid.17091.3e, ISNI 0000 0001 2288 9830, Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, , The University of British Columbia, ; Vancouver, BC V6T 1Z3 Canada

[10 ]GRID grid.411405.5, ISNI 0000 0004 1757 8861, Department of Neurology, , Huashan Hospital, Fudan University, ; 200040 Shanghai, China

[11 ]GRID grid.410570.7, ISNI 0000 0004 1760 6682, Chongqing Key Laboratory of Ageing and Brain Diseases, Daping Hospital, , Third Military Medical University, ; 400042 Chongqing, China

[12 ]GRID grid.9227.e, ISNI 0000000119573309, Center for Excellence in Brain Science and Intelligence Technology, , Chinese Academy of Sciences, ; 200031 Shanghai, China

Author information

Xian-Le Bu http://orcid.org/0000-0002-2331-3339

Xiao-Wei Chen http://orcid.org/0000-0003-0906-6666

Weihong Song http://orcid.org/0000-0001-9928-889X

Yan-Jiang Wang http://orcid.org/0000-0002-6227-6112

Article

Publisher ID: 918

DOI: 10.1038/s41398-020-00918-y

PMC ID: 7359297

PubMed ID: 32661266

SO-VID: 6fd222ef-a96b-40de-ad8b-44d5f46c54bb

License:

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