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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Age Factors
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Ferric Compounds*
  • Humans
  • Imaging, Three-Dimensional
  • Metal Nanoparticles*
  • Mice
  • Mice, Transgenic
  • Microglia / metabolism
  • Microglia / pathology*
  • Microglia / ultrastructure
  • Mutation / genetics
  • NF-kappa B / metabolism*
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use
  • Plaque, Amyloid / pathology*
  • Presenilin-1 / genetics
  • Resveratrol
  • Stilbenes / chemistry
  • Stilbenes / pharmacology
  • Stilbenes / therapeutic use


  • Amyloid beta-Protein Precursor
  • Enzyme Inhibitors
  • Ferric Compounds
  • NF-kappa B
  • Neuroprotective Agents
  • PSEN1 protein, human
  • Presenilin-1
  • Stilbenes
  • ferric oxide
  • Resveratrol