Abstract
Methylxanthines (MTX) are alkaloids derived from the purine-base xanthine. Whereas especially caffeine, the most prominent known MTX, has been formerly assessed to be detrimental, this point of view has changed substantially. MTXs are discussed to have beneficial properties in neurodegenerative diseases, however, the mechanisms of action are not completely understood. Here we investigate the effect of the naturally occurring caffeine, theobromine and theophylline and the synthetic propentofylline and pentoxifylline on processes involved in Alzheimer’s disease (AD). All MTXs decreased amyloid-β (Aβ) level by shifting the amyloid precursor protein (APP) processing from the Aβ-producing amyloidogenic to the non-amyloidogenic pathway. The α-secretase activity was elevated whereas β-secretase activity was decreased. Breaking down the molecular mechanism, caffeine increased protein stability of the major α-secretase ADAM10, downregulated BACE1 expression and directly decreased β-secretase activity. Additionally, APP expression was reduced. In line with literature, MTXs reduced oxidative stress, decreased cholesterol and a decreased in Aβ1-42 aggregation. In conclusion, all MTXs act via the pleiotropic mechanism resulting in decreased Aβ and show beneficial properties with respect to AD in neuroblastoma cells. However, the observed effect strength was moderate, suggesting that MTXs should be integrated in a healthy diet rather than be used exclusively to treat or prevent AD.
Highlights
Alzheimer’s disease (AD), the most common form of dementia in the elderly population, affects approximately 45 million people worldwide, emphasizing AD as a major public health concern [1,2].Aging of the population is the main risk factor for suffering AD in industrialized nations highlighting the need to delay the disease onset
The aim of the study was to (I) further elucidate the molecular mechanism especially of caffeine on the protective effect in respect to AD focusing on the Aβ metabolism and (II) compare these effects with the other two mainly naturally occurring MTXs theophylline and theobromine and two synthetic MTXs propentofylline and pentoxifylline widely used as a drug having a higher affinity to adenosine receptors compared to the naturally occurring MTXs
Caffeine and theophylline were purchased from Fisher Scientific (Schwerte, Germany), theobromine, pentoxifylline, propentofylline and all other chemicals used in this study were acquired from Merck former Sigma-Aldrich (Darmstadt, Germany), if not stated otherwise
Summary
Alzheimer’s disease (AD), the most common form of dementia in the elderly population, affects approximately 45 million people worldwide, emphasizing AD as a major public health concern [1,2].Aging of the population is the main risk factor for suffering AD in industrialized nations (world health organization. www.who.int/ageing/publications/global_health) highlighting the need to delay the disease onset. Aging of the population is the main risk factor for suffering AD in industrialized nations Www.who.int/ageing/publications/global_health) highlighting the need to delay the disease onset. The β-CTF is further processed by γ-secretase, generating Aβ peptides with variable C-terminus, mainly Aβ38, Aβ39, Aβ40 and Aβ42 peptides [10,11], and the APP intracellular domain (AICD) which is discussed to regulate gene transcription [12,13,14,15,16,17]. Aβ peptides can be either degraded mainly by neprilysin or insulin-degrading enzyme (IDE) [18,19], or can aggregate to amyloid senile plaques in the brains of individuals suffering from AD.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
