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Optical and SPION-enhanced MR imaging shows that trans-stilbene inhibitors of NF-?B concomitantly lower Alzheimer's disease plaque formation and microglial activation in A?PP/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-? (A?). Activation of microglia, which closely associate with A? plaques, engenders the release of pro-inflammatory cytokines and the internalization of A? fibrils. Since the pro-inflammatory transcription factor NF-?B is one of the major regulators of A?-induced inflammation, we treated transgenic amyloid-? protein protein/presenilin-1 (A?PP/PS1) mice for one year with a low dose (0.01% by weight in the diet) of either of two trans-stilbene NF-?B inhibitors, resveratrol or a synthetic analog LD55. The 3D distribution of A? plaques was measured ex vivo in intact brains at 60 ?m resolution by quantitative magnetic resonance imaging (MRI) using blood-brain barrier-permeable, anti-A?PP-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 A? 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 A? 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 A? plaque burden and neuroinflammation to a similar extent, it appears that the antioxidant potential of resveratrol is not an important factor in plaque reduction.

SUBMITTER: Solberg NO

PROVIDER: S-EPMC4407807 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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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.

Solberg Nathan O NO Chamberlin Ryan R Vigil Jenette R JR Deck Lorraine M LM Heidrich John E JE Brown David C DC Brady Christina I CI Vander Jagt Thomas A TA Garwood Michael M Bisoffi Marco M Severns Virginia V Vander Jagt David L DL Sillerud Laurel O LO

Journal of Alzheimer's disease : JAD 20140101 1

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) mi ...[more]

PMID: 24413613

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Project description:Current risk stratification for stroke is still based upon percentage of carotid stenosis, despite this measure providing minimal patient-specific information on the actual risk of stroke for both symptomatic individuals without significant carotid artery stenosis as well as asymptomatic carotid stenosis patients. A continuously growing body of literature suggests that the identification and quantification of certain carotid plaque characteristics, including lipid-rich necrotic core (LRNC), thin/ruptured fibrous cap (FC), and intraplaque hemorrhage (IPH), provide a superior means of predicting future stroke. These characteristics are identifiable via magnetic resonance imaging (MRI), with most features detectable using commercially available coils and sequences utilized in routine clinical practice in as little as 4 minutes. The presence of LRNC, a thin/ruptured FC, and IPH is associated with increased risk of future stroke or TIA. Plaques with greater than 40% LRNC with a thin overlying FC are prone to rupture. LRNC is T2 hypointense and lacks enhancement on contrast enhanced T1 weighted images. Increasing LRNC size is associated with the development of new ulceration, FC rupture, increasing plaque burden, as well as fatal and nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome (ACS), and symptom-driven revascularization, allowing for MR biomarkers of carotid plaque vulnerability to be utilized for systemic athero-thrombotic risk and not just stroke/TIA. LRNC typically shrinks with appropriate statin therapy, with PCSK9 inhibitors possibly playing a role in patients with inadequate response. Carotid plaques with IPH represent a more advanced stage of atherosclerotic disease. IPH is detectable with field strengths of both 3.0 T and 1.5 T and will demonstrate high signal on all T1 weighted imaging sequences. The presence of IPH increases the risk of future stroke in both symptomatic and asymptomatic patients, with multivariate analysis identifying IPH as a predictor of stroke, independent of percent stenosis, with no statistical difference in men vs. women, demonstrating that simple carotid stenosis measurements and traditional risk factor analysis may be inadequate in identifying patients at the highest risk for adverse cerebrovascular events. In the evaluation for recurrent stroke in recently symptomatic patients with >50% carotid stenosis, the estimated annual stroke risk is 23.2% in IPH+ patients and only 0.6% in IPH- patients, calling into question the current risk-benefit assessment for CEA. Additionally, a recent meta-analysis suggests that IPH+ plaque in patients with symptomatic <50% stenosis may be the etiology of embolic strokes previously labeled as "embolic stroke of undetermined source" (ESUS). There are no prospective drug trials testing the ability of any lipid-lowering therapies to decrease IPH and/or total plaque volume (TPV). Given the continuously increasing evidence of IPH as a significant predictor of carotid plaque progression and future adverse vascular events, trials aimed at targeted therapy for IPH represents a significant need.

Dataset Information

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

Publications

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.

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