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J Biol Chem. 2018 Nov 23;293(47):18242-18269. doi: 10.1074/jbc.RA117.001245. Epub 2018 Oct 3.

Mini-GAGR, an intranasally applied polysaccharide, activates the neuronal Nrf2-mediated antioxidant defense system.

Author information

1
From the Departments of Neurosciences and.
2
Pathology, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio 43614 and.
3
the Department of Chemical Engineering, College of Engineering, University of Toledo, Toledo, Ohio 43607.
4
From the Departments of Neurosciences and joshua.park2@utoledo.edu.

Abstract

Oxidative stress triggers and exacerbates neurodegeneration in Alzheimer's disease (AD). Various antioxidants reduce oxidative stress, but these agents have little efficacy due to poor blood-brain barrier (BBB) permeability. Additionally, single-modal antioxidants are easily overwhelmed by global oxidative stress. Activating nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) and its downstream antioxidant system are considered very effective for reducing global oxidative stress. Thus far, only a few BBB-permeable agents activate the Nrf2-dependent antioxidant system. Here, we discovered a BBB-bypassing Nrf2-activating polysaccharide that may attenuate AD pathogenesis. Mini-GAGR, a 0.7-kDa cleavage product of low-acyl gellan gum, increased the levels and activities of Nrf2-dependent antioxidant enzymes, decreased reactive oxygen species (ROS) under oxidative stress in mouse cortical neurons, and robustly protected mitochondria from oxidative insults. Moreover, mini-GAGR increased the nuclear localization and transcriptional activity of Nrf2 similarly to known Nrf2 activators. Mechanistically, mini-GAGR increased the dissociation of Nrf2 from its inhibitor, Kelch-like ECH-associated protein 1 (Keap1), and induced phosphorylation and nuclear translocation of Nrf2 in a protein kinase C (PKC)- and fibroblast growth factor receptor (FGFR1)-dependent manner. Finally, 20-day intranasal treatment of 3xTg-AD mice with 100 nmol of mini-GAGR increased nuclear p-Nrf2 and growth-associated protein 43 (GAP43) levels in hippocampal neurons, reduced p-tau and β-amyloid (Aβ) peptide-stained neurons, and improved memory. The BBB-bypassing Nrf2-activating polysaccharide reported here may be effective in reducing oxidative stress and neurodegeneration in AD.

KEYWORDS:

Alzheimer disease; BBB-bypassing polysaccharide; amyloid; antioxidant; antioxidant enzymes; mini-GAGR; neurodegeneration; nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2); oxidative stress; polysaccharide; tau

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