Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that has proved refractory to drug treatment. Given evidence of neuroprotection in animal models of ischemic stroke, we assessed the prenylflavonoid xanthohumol from the Common Hop (Humulus lupulus L.) for therapeutic potential in murine neuroblastoma N2a cells stably expressing human Swedish mutant amyloid precursor protein (N2a/APP), a well-characterized cellular model of AD. The ELISA and Western-blot analysis revealed that xanthohumol (Xn) inhibited Aβ accumulation and APP processing, and that Xn ameliorated tau hyperphosphorylation via PP2A, GSK3β pathways in N2a/APP cells. The amelioration of tau hyperphosphorylation by Xn was also validated on HEK293/Tau cells, another cell line with tau hyperphosphorylation. Proteomic analysis (2D-DIGE-coupled MS) revealed a total of 30 differentially expressed lysate proteins in N2a/APP vs. wild-type (WT) N2a cells (N2a/WT), and a total of 21 differentially expressed proteins in lysates of N2a/APP cells in the presence or absence of Xn. Generally, these 51 differential proteins could be classified into seven main categories according to their functions, including: endoplasmic reticulum (ER) stress-associated proteins; oxidative stress-associated proteins; proteasome-associated proteins; ATPase and metabolism-associated proteins; cytoskeleton-associated proteins; molecular chaperones-associated proteins, and others. We used Western-blot analysis to validate Xn-associated changes of some key proteins in several biological/pathogenic processes. Taken together, we show that Xn reduces AD-related changes in stably transfected N2a/APP cells. The underlying mechanisms involve modulation of multiple pathogenic pathways, including those involved in ER stress, oxidative stress, proteasome molecular systems, and the neuronal cytoskeleton. These results suggest Xn may have potential for the treatment of AD and/or neuropathologically related neurodegenerative diseases.
Highlights
Xanthohumol (Xn) is the abundant prenylated polyphenol, or chalcone (Figure 1A), in cones of the Common Hop (Humulus lupulus L.), a species of flowering plant native to temperate regions of the Northern Hemisphere
Compared with vehicle control (0.5% DMSO), no difference in cell viability was observed in N2a/WT cells treated for 24 h with less than or equal to 12.5 μM Xn (Figure 1B)
We identified some coincident proteins in the four comparison pairs, including endoplasmic reticulum (ER) stress-related proteins, protein disulfide-isomerase (PDA1), proteasomerelated proteins, 26S protease regulatory subunit 10B (PRS10) and 26S protease regulatory subunit 8 (PRS8), energy metabolism-related protein, ATP synthase subunit alpha (ATPA), and transketolase (TKT) and alpha-enolase (ENOA)
Summary
Xanthohumol (Xn) is the abundant prenylated polyphenol, or chalcone (Figure 1A), in cones of the Common Hop (Humulus lupulus L.), a species of flowering plant native to temperate regions of the Northern Hemisphere. The Michael Acceptor of this chalcone irreversibly binds to and modifies cysteine residues of proteins, such as those involved in the NF-κB activation pathway, which is inhibited by Harikumar et al (2009). Both of these chemical properties appear to underwrite the poly-pharmacological activities of Xn, including anti-proliferation (Deeb et al, 2010), anti-inflammation (Dorn et al, 2013), and anti-adipogenesis (Yang et al, 2007). The neuroprotective effects of Xn have been attributed to its free-radical scavenging property, the chalcone positively modulates central regulators of cellular redox and energy balance via actions on endoplasmic reticulum (ER) (activation of nuclear factor E2-related factor 2: Nrf2) and mitochondria (activation of AMP-activated kinase: AMPK) in mouse fibroblasts (Zimmermann et al, 2015)
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