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

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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Overproduction of Aβ plays a key role in the pathogenesis of AD. Aβ is derived from sequential cleavage of APP by β-secretase and γ-secretase within neurons, and then secreted to extracellular space.  ADAM10 is the major α-secretase that catalyses α-cleavage and promotes non-amyloidogenic processing of APP. ADAM10 is first generated as an inactive proenzyme (proADAM10) and matures into an active protease after the removal of its prodomain. We found that capsaicin treatment significantly increased brain levels of matADAM10 relative to APP/PS1 controls but did not affect proADAM10 protein or mRNA expression, suggesting that capsaicin increases the level of ADAM10 by promoting its maturation or activation. 

Capsaicin, as a natural component of spicy food, has potential advantages as an AD intervention strategy. Considering that chili peppers have been a vital part of culinary cultures worldwide and have a long history of application for flavouring, they are feasible to utilized for AD prevention. In addition, capsaicin is a potential therapeutic molecule for various human diseases, such as obesity, cardiovascular diseases, hypertension, and atherosclerosis, which are established risk factors for AD. Taken together, the current and previous findings suggest capsaicin may prevent AD by targeting multiple pathways that drive the pathogenesis of AD. (Translational Psychiatry volume 10, Article number: 230 (2020))