title: 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.
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.
authors.affiliation: Departments of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM, USA.
authors.forename: Nathan O
authors.initials: NO
authors.lastname: Solberg
authors.affiliation: The Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Chamberlin
authors.affiliation: Departments of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM, USA.
authors.forename: Jenette R
authors.initials: JR
authors.lastname: Vigil
authors.affiliation: Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM, USA.
authors.forename: Lorraine M
authors.initials: LM
authors.lastname: Deck
authors.affiliation: Quatros LLC, Albuquerque, NM, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Heidrich
authors.affiliation: Departments of Pathology, University of New Mexico School of Medicine, Albuquerque, NM, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Brown
authors.affiliation: Departments of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM, USA.
authors.forename: Christina I
authors.initials: CI
authors.lastname: Brady
authors.affiliation: Quatros LLC, Albuquerque, NM, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Vander Jagt
authors.affiliation: The Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Garwood
authors.affiliation: Departments of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Bisoffi
authors.affiliation: Departments of Pathology, University of New Mexico School of Medicine, Albuquerque, NM, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Severns
authors.affiliation: Departments of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM, USA Quatros LLC, Albuquerque, NM, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Vander Jagt
authors.affiliation: Departments of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM, USA.
authors.forename: Laurel O
authors.initials: LO
authors.lastname: Sillerud
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005290:Ferric Compounds; D006801:Humans; D021621:Imaging, Three-Dimensional; D053768:Metal Nanoparticles; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D058225:Plaque, Amyloid / Q000473:pathology*; D053764:Presenilin-1 / Q000235:genetics; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D005290:Ferric Compounds; D016328:NF-kappa B; D018696:Neuroprotective Agents; C508853:PSEN1 protein, human; D053764:Presenilin-1; D013267:Stilbenes; C000499:ferric oxide; D000077185:Resveratrol
keywords: LD55; NF-κB; SPIONs; magnetic resonance imaging; microglia; neuroinflammation; resveratrol; transgenic mice