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

Nathan O. Solberg, Ryan Chamberlin, Jenette R. Vigil, Lorraine M. Deck, John E. Heidrich, David C. Brown, Christina I. Brady, Thomas A. Vander Jagt, Michael Garwood, Marco Bisoffi, Virginia Severns, David L.Vander Jagt, Laurel O. Sillerud

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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. Supplementary Materials. JAD131031-supplemental.figure.5A.nb Supplementary Materials. JAD131031-supplemental.figure.5B.nb Supplementary Materials.

Original languageEnglish (US)
Pages (from-to)191-212
Number of pages22
JournalJournal of Alzheimer's Disease
Volume40
Issue number1
DOIs
StatePublished - 2014

Keywords

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

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