Investigating the Neuroprotective Effects of Turmeric Extract: Structural Interactions of β-Amyloid Peptide with Single Curcuminoids

Abstract

A broad biophysical analysis was performed to investigate the molecular basis of the neuroprotective action of Curcuma longa extracts in Alzheimer’s disease. By combining circular dichroism and electron paramagnetic resonance experiments with molecular modeling calculations, the minor components of Curcuma longa extracts, such as demethoxycurcumin (2, DMC), bisdemethoxycurcumin (3, BDMC) and cyclocurcumin (4, CYC), were analyzed in a membrane environment mimicking the phospholipid bilayer. Our study provides the first evidence on the relative role of single curcuminoids interacting with Aβ-peptide. When the CYC and curcumin metabolite tetrahydrocurcumin (5, THC) were inserted into an anionic lipid solution, a significant modification of the Aβ CD curves was detected. These data were implemented by EPR experiments, demonstrating that CYC reaches the inner part of the bilayer, while the other curcuminoids are localized close to the membrane interface. Computational studies provided a model for the curcuminoid-Aβ interaction, highlighting the importance of a constrained “semi-folded” conformation to interact with Aβ analogously to the pattern observed in α-helical coiled-coil peptide structures. This combined approach led to a better understanding of the intriguing in vitro and in vivo activity of curcuminoids as anti-Alzheimer agents, paving a new path for the rational design of optimized druggable analogues.

Curcumin, demethoxycurcumin, and bisdemethoxycurcumin induced caspase-dependent and –independent apoptosis via Smad or Akt signaling pathways in HOS cells

“…The three major chemical constituents and biological activities of turmeric were approximately 77% curcumin (CUR), 17% demethoxycurcumin (DMC), and 3% bisdemethoxycurcumin (BDMC), which are belong to curcuminoids [1,2]. Cur, a linear diarylheptanoid, is a natural phenolic compound and it has been well known and used to treat many diseases, such as cancer [3][4][5][6], diabetes [7,8], inflammation [1] and neurodegenerative disorders [9,10]. In spite of the potential health benefits of CUR, its clinical applications are limited due to its low oral bioavailability, low water solubility, and instability at acidic Ph [11,12].…”

Inhibitory effects of curcumin and cyclocurcumin in 1-methyl-4-phenylpyridinium (MPP+) induced neurotoxicity in differentiated PC12 cells

“…Randino et al . have studied the interaction of cyclocurcumin with Aβ peptides in vitro in anionic lipid solution to shed light on how cyclocurcumin can be effective in treating Alzheimer’s disease (AD) 50 . Though the study is interesting, it would have provided more light on the effect of cyclocurcumin in AD if it had been conducted in AD cell model.…”

Curcumin in Health and Diseases: Alzheimer’s Disease and Curcumin Analogues, Derivatives, and Hybrids

“…Randino et al [72] studied the structural interactions of amyloid-β peptide with single curcuminoids. Their computer-aided studiessuggested a model for the Aβ interaction of curcuminoids.…”