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

Article type: Research Article

Authors: Solberg, Nathan O.^a | Chamberlin, Ryan^e | Vigil, Jenette R.^a | Deck, Lorraine M.^c | Heidrich, John E.^d | Brown, David C.^b | Brady, Christina I.^a | Vander Jagt, Thomas A.^d | Garwood, Michael^e | Bisoffi, Marco^a | Severns, Virginia^b | Vander Jagt, David L.^{a; d} | Sillerud, Laurel O.^{a; *}

Affiliations: [a] Departments of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM, USA | [b] Departments of Pathology, University of New Mexico School of Medicine, Albuquerque, NM, USA | [c] Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM, USA | [d] Quatros LLC, Albuquerque, NM, USA | [e] The Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota Medical School, Minneapolis, MN, USA

Correspondence: [*] Correspondence to: Laurel O. Sillerud, Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, USA. E-mail: [email protected].

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

DOI: 10.3233/JAD-131031

Journal: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 191-212, 2014