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Chronic treatment with a smart antioxidative nanoparticle for inhibition of amyloid plaque propagation in Tg2576 mouse model of Alzheimer's disease.

ABSTRACT: The present study aimed to assess whether our newly developed redox nanoparticle (RNP^N) that has antioxidant potential decreases A? levels or prevents A? aggregation associated with oxidative stress. The transgenic Tg2576 Alzheimer's disease (AD) mice were used to investigate the effect of chronic ad libitum drinking of RNP^N solution for 6 months, including memory and learning functions, antioxidant activity, and amyloid plaque aggregation. The results showed that RNP^N-treated mice had significantly attenuated cognitive deficits of both spatial and non-spatial memories, reduced oxidative stress of lipid peroxide, and DNA oxidation. RNP^N treatment increased the percent inhibition of superoxide anion and glutathione peroxidase activity, neuronal densities in the cortex and hippocampus, decreased A?(1-40), A?(1-42) and gamma (?)-secretase levels, and reduced A? plaque observed using immunohistochemistry analysis and thioflavin S staining. Our results suggest that RNP^N may be a promising candidate for AD therapy because of its antioxidant properties and reduction in A? aggregation, thereby suppressing its adverse side effect.

SUBMITTER: Boonruamkaew P

PROVIDER: S-EPMC5476667 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Chronic treatment with a smart antioxidative nanoparticle for inhibition of amyloid plaque propagation in Tg2576 mouse model of Alzheimer's disease.

Boonruamkaew Phetcharat P Chonpathompikunlert Pennapa P Vong Long Binh LB Sakaue Sho S Tomidokoro Yasushi Y Ishii Kazuhiro K Tamaoka Akira A Nagasaki Yukio Y

Scientific reports 20170619 1

The present study aimed to assess whether our newly developed redox nanoparticle (RNPN) that has antioxidant potential decreases Aβ levels or prevents Aβ aggregation associated with oxidative stress. The transgenic Tg2576 Alzheimer's disease (AD) mice were used to investigate the effect of chronic ad libitum drinking of RNPN solution for 6 months, including memory and learning functions, antioxidant activity, and amyloid plaque aggregation. The results showed that RNPN ...[more]

PMID: 28630497

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Project description:One century after its first description, pathology of Alzheimer's disease (AD) is still poorly understood. Amyloid-related dendritic atrophy and membrane alterations of susceptible brain neurons in AD, and in animal models of AD are widely recognized. However, little effort has been made to study the potential effects of combined morphological and membrane alterations on signal transfer and synaptic integration in neurons that build up affected neural networks in AD. In this study spatial reconstructions and electrophysiological measurements of layer II/III pyramidal neurons of the somatosensory cortex from wild-type (WT) and transgenic (TG) human amyloid precursor protein (hAPP) overexpressing Tg2576 mice were used to build faithful segmental cable models of these neurons. Local synaptic activities were simulated in various points of the dendritic arbors and properties of subthreshold dendritic impulse propagation and predictors of synaptic input pattern recognition ability were quantified and compared in modeled WT and TG neurons. Despite the widespread dendritic degeneration and membrane alterations in mutant mouse neurons, surprisingly little, or no change was detected in steady-state and 50 Hz sinusoidal voltage transfers, current transfers, and local and propagation delays of PSPs traveling along dendrites of TG neurons. Synaptic input pattern recognition ability was also predicted to be unaltered in TG neurons in two different soma-dendritic membrane models investigated. Our simulations predict the way how subthreshold dendritic signaling and pattern recognition are preserved in TG neurons: amyloid-related membrane alterations compensate for the pathological effects that dendritic atrophy has on subthreshold dendritic signal transfer and integration in layer II/III somatosensory neurons of this hAPP mouse model for AD. Since neither propagation of single PSPs nor integration of multiple PSPs (pattern recognition) changes in TG neurons, we conclude that AD-related neuronal hyperexcitability cannot be accounted for by altered subthreshold dendritic signaling in these neurons but hyperexcitability is related to changes in active membrane properties and network connectivity.

Project description:In a positron-emission tomography (PET) study with the β-amyloid (Aβ) tracer [(18)F]-florbetaben, we previously showed that Aβ deposition in transgenic mice expressing Swedish mutant APP (APP-Swe) mice can be tracked in vivo. γ-Secretase modulators (GSMs) are promising therapeutic agents by reducing generation of the aggregation prone Aβ42 species without blocking general γ-secretase activity. We now aimed to investigate the effects of a novel GSM [8-(4-Fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine (RO5506284) displaying high potency in vitro and in vivo on amyloid plaque burden and used longitudinal Aβ-microPET to trace individual animals. Female transgenic (TG) APP-Swe mice aged 12 months (m) were assigned to vehicle (TG-VEH, n=12) and treatment groups (TG-GSM, n=12), which received daily RO5506284 (30 mg kg(-1)) treatment for 6 months. A total of 131 Aβ-PET recordings were acquired at baseline (12 months), follow-up 1 (16 months) and follow-up 2 (18 months, termination scan), whereupon histological and biochemical analyses of Aβ were performed. We analyzed the PET data as VOI-based cortical standard-uptake-value ratios (SUVR), using cerebellum as reference region. Individual plaque load assessed by PET remained nearly constant in the TG-GSM group during 6 months of RO5506284 treatment, whereas it increased progressively in the TG-VEH group. Baseline SUVR in TG-GSM mice correlated with Δ%-SUVR, indicating individual response prediction. Insoluble Aβ42 was reduced by 56% in the TG-GSM versus the TG-VEH group relative to the individual baseline plaque load estimates. Furthermore, plaque size histograms showed differing distribution between groups of TG mice, with fewer small plaques in TG-GSM animals. Taken together, in the first Aβ-PET study monitoring prolonged treatment with a potent GSM in an AD mouse model, we found clear attenuation of de novo amyloidogenesis. Moreover, longitudinal PET allows non-invasive assessment of individual plaque-load kinetics, thereby accommodating inter-animal variations.

Dataset Information

Chronic treatment with a smart antioxidative nanoparticle for inhibition of amyloid plaque propagation in Tg2576 mouse model of Alzheimer's disease.

Publications

Chronic treatment with a smart antioxidative nanoparticle for inhibition of amyloid plaque propagation in Tg2576 mouse model of Alzheimer's disease.

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