Effect of Caffeine and Other Methylxanthines on Aβ-Homeostasis in SH-SY5Y Cells

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.

Potential of Caffeine in Alzheimer’s Disease—A Review of Experimental Studies

“…Numerous mechanisms of caffeine action, which may be relevant to its favorable effects in AD models were demonstrated in studies on cell cultures. For example, in vitro caffeine decreased Aβ level and Aβ 1-42 deposition, and reduced BACE-1 activity in human neuroblastoma SH-SY5Y cells [ 182 ], and inhibited oligomerization of Aβ in N2a/APP cells [ 183 ]. Also decreased expression of BACE-1 and APP was demonstrated after caffeine treatment in human neuroblastoma SH-SY5Y cells exposed to AlCl 3 and Aβ [ 164 ].…”

Methylxanthines Inhibit Primary Amine Oxidase and Monoamine Oxidase Activities of Human Adipose Tissue

“…While this is clearly significant, it remains speculative until detailed studies with pure enzyme are carried out. Nonetheless, it is known that these compounds have a wide variety of health benefits when present in the diet, especially on neurodegenerative disease [4,5,60,61] and must, therefore, reach levels sufficient to exert pharmacological action. The true levels of methylxanthine interacting with the enzyme under the conditions of this study were impossible to estimate due to the possibility of interaction with lipids and tissue components.…”

The impact of capsaicinoids on APP processing in Alzheimer’s disease in SH-SY5Y cells

“…Protein amount was adjusted to 5 mg/mL for rafts and 2 mg/mL for membrane isolation. The latter were then centrifuged at 900 rcf for 10 min at 4 °C and supernatants containing postnuclear fractions (PNFs) were collected 34 . Homogenates were stored at −80 °C.…”

“…Several Aβ-lowering dietary components, bioactive compounds or supplements have been described, e.g. DHA, vitamin D and vitamin D analogues, polyphenols, caffeine and some phytosterols [30][31][32][33][34][35][36] . Recently, capsaicin, found in Capsicum species and spices consumed worldwide, has been proposed to be potentially beneficial in respect to tau alterations of AD in patients suffering from type 2 diabetes, known as risk factor for the development of AD 37,38 .…”