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J Alzheimers Dis. 2014;40(1):191-212. doi: 10.3233/JAD-131031.

Optical and SPION-enhanced MR imaging shows that trans-stilbene inhibitors of NF-κB concomitantly lower Alzheimer's disease plaque formation and microglial activation in AβPP/PS-1 transgenic mouse brain.

Author information

1
Departments of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM, USA.
2
The Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota Medical School, Minneapolis, MN, USA.
3
Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM, USA.
4
Quatros LLC, Albuquerque, NM, USA.
5
Departments of Pathology, University of New Mexico School of Medicine, Albuquerque, NM, USA.
6
Departments of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM, USA Quatros LLC, Albuquerque, NM, USA.

Abstract

Alzheimer's disease (AD) is associated with a microglia-dependent neuroinflammatory response against plaques containing the fibrous protein amyloid-β (Aβ). Activation of microglia, which closely associate with Aβ plaques, engenders the release of pro-inflammatory cytokines and the internalization of Aβ fibrils. Since the pro-inflammatory transcription factor NF-κB is one of the major regulators of Aβ-induced inflammation, we treated transgenic amyloid-β protein protein/presenilin-1 (AβPP/PS1) mice for one year with a low dose (0.01% by weight in the diet) of either of two trans-stilbene NF-κB inhibitors, resveratrol or a synthetic analog LD55. The 3D distribution of Aβ plaques was measured ex vivo in intact brains at 60 μm resolution by quantitative magnetic resonance imaging (MRI) using blood-brain barrier-permeable, anti-AβPP-conjugated superparamagentic iron oxide nanoparticles (SPIONs). The MRI measurements were confirmed by optical microscopy of thioflavin-stained brain tissue sections and indicated that supplementation with either of the two trans-stilbenes lowered Aβ plaque density in the cortex, caudoputamen, and hippocampus by 1.4 to 2-fold. The optical measurements also included the hippocampus and indicated that resveratrol and LD55 reduced average Aβ plaque density by 2.3-fold and 3.1-fold, respectively. Ex vivo measurements of the regional distribution of microglial activation by Iba-1 immunofluorescence of brain tissue sections showed that resveratrol and LD55 reduced average microglial activation by 4.2- fold and 3.5-fold, respectively. Since LD55 lacked hydroxyl groups but both resveratrol and LD55 concomitantly reduced both Aβ plaque burden and neuroinflammation to a similar extent, it appears that the antioxidant potential of resveratrol is not an important factor in plaque reduction.

KEYWORDS:

LD55; NF-κB; SPIONs; magnetic resonance imaging; microglia; neuroinflammation; resveratrol; transgenic mice

PMID:
24413613
PMCID:
PMC4407807
DOI:
10.3233/JAD-131031
[Indexed for MEDLINE]
Free PMC Article

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