In vivo evaluation of a hybrid nanoparticle for molecular imaging of amyloid aggregation

International audienceAmyloid-β (Aβ) fibrillization is described as a central event in the pathogenesis of Alzheimer’s disease (AD). Amyloid imaging is expected to play a pivotal role in early and differential diagnosis of dementias, and in the evaluation of anti-Aβ treatments. Luminescent conjugated oligothiophenes (LCO) have been proposed as optical biomarkers of protein fibrillation [1]. In this paper, we evaluated a fluorescent magnetic hybrid nanoprobe (HNP5011), based on gadolinium fluoride nanoparticles functionalized with luminescent conjugated polythiophenes moieties (Fig. 1). The aim of this study was to investigate its potential for molecular imaging in a rat model bearing intracerebral pre-aggregated Aβ peptides

Increased hippocampal CA1 density of serotonergic terminals in a triple transgenic mouse model of Alzheimer's disease: an ultrastructural study

Alzheimer's disease (AD) is a neurodegenerative pathology that deteriorates mnesic functions and associated brain regions including the hippocampus. Serotonin (5-HT) has an important role in cognition. We recently demonstrated an increase in 5-HT transporter (SERT) fibre density in the hippocampal CA1 in an AD triple transgenic mouse model (3xTg-AD). Here, we analyse the ultrastructural localisation, distribution and numerical density (Nv) of hippocampal SERT axons (SERT-Ax) and terminals (SERT-Te) and their relationship with SERT fibre sprouting and altered synaptic Nv in 3xTg-AD compared with non-transgenic control mice. 3xTg-AD animals showed a significant increase in SERT-Te Nv in CA1 at both, 3 (95%) and 18 months of age (144%), being restricted to the CA1 stratum moleculare (S. Mol; 227% at 3 and 180% at 18 months). 3xTg-AD animals also exhibit reduced Nv of perforated axospinous synapses (PS) in CA1 S. Mol (56% at 3 and 52% at 18 months). No changes were observed in the Nv of symmetric and asymmetrical synapses or SERT-Ax. Our results suggest that concomitant SERT-Te Nv increase and PS reduction in 3xTg-AD mice may act as a compensatory mechanism maintaining synaptic efficacy as a response to the AD cognitive impairment

GABAA receptor density is altered by cannabinoid treatment in the hippocampus of adult but not adolescent rats.

Cannabinoids are known to induce transient psychotic symptoms and cognitive dysfunction in healthy individuals and contribute to trigger schizophrenia in vulnerable individuals, particularly during adolescence. Converging preclinical evidence suggests important interactions between cannabinoid and GABAergic systems. In the present study, we compared the effects of cannabinoid treatment on GABAA receptor binding in the brain of adolescent and adult rats. Adolescent (5weeks old) and adult (10weeks old) rats were treated with the synthetic cannabinoid HU210 (25, 50 or 100I14g/kg/day) or vehicle for 1, 4 or 14days. Rats were sacrificed 24h after the last injection and GABAA receptor density was measured in several brain regions using [35S]TBPS and in vitro autoradiography. Adolescent rats had higher numbers of GABAA receptors compared to adults. A 24% increase of binding in adult rats treated with 100I14g/kg HU210 for 14days compared to controls was observed in the CA1 region of the hippocampus (16.1 versus 12.9fmol/mg tissue equivalent, t =2.720, p <0.05). HU210 did not affect GABAA receptors in adolescent rats in any treatment regimen and in adult rats treated with HU210 for 1 or 4days. These data suggest that long-term, high-dose treatment with HU210 increases GABAA receptors in the hippocampus of adult rats, changes that may interfere with associated hippocampal cognitive functions such as learning and memory. In addition, our results suggest that the adolescent brain does not display the same compensatory mechanisms that are activated in the adult brain following cannabinoid treatment. © 2010, Elsevier Ltd

Differential Treatment Regimen-Related Effects of HU210 on CB(1) and D(2)-Like Receptor Functionality in the Rat Basal Ganglia

Background/Aims: Functional linkages between the cannabinoid CB(1) and the dopaminergic systems have been reported although the observations and the mechanisms hypothesizing their interactions at the G protein-coupled receptor (GPCR) functionality level are conflicting. Methods: Administration of a potent cannabinoid agonist, HU210, at various doses (25-100 μg/kg) and treatment regimens (1- to 14-day treatment) in rats was carried out to investigate the effect of HU210 treatment on the CB(1) and D(2)-like agonist-mediated GPCR activation. Results: The desensitizations (reduced coupling) of both D(2) agonist- and CB(1) agonist-mediated GPCR activation was found to be treatment duration dependent and region specific, suggesting implication of receptor tolerance and adaptation due to the cannabinoid treatment. The effect of HU210 on the CB(1) agonist-mediated GPCR desensitization in all treatment groups was not dose dependent. Conclusions: The desensitization of D(2)-like receptors found after a cannabinoid treatment in this study strengthens the evidence that the two neurotransmitter systems interact at the intercellular level; this interaction might occur via multiple mechanisms, which also vary according to region. Copyright © 2012 S. Karger AG, Basel

Longitudinal consequences of hippocampal amyloid-beta fibrils injections on 5-HT1A receptors: an in vitro autoradiography study

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Synergistic Effect between Maternal Infection and Adolescent Cannabinoid Exposure on Serotonin 5HT1A Receptor Binding in the Hippocampus: Testing the “Two Hit” Hypothesis for the Development of Schizophrenia

Infections during pregnancy and adolescent cannabis use have both been identified as environmental risk factors for schizophrenia. We combined these factors in an animal model and looked at their effects, alone and in combination, on serotonin 5 H T 1 A receptor binding (5 H T 1 A R ) binding longitudinally from late adolescence to adulthood. Pregnant rats were exposed to the viral mimic poly I:C on embryonic day 15. Adolescent offspring received daily injections of the cannabinoid HU210 for 14 days starting on postnatal day (PND) 35. Hippocampal and cortical 5 H T 1 A R binding was quantified autoradiographically using [3H]8-OH-DPAT, in late adolescent (PND 55), young adult (PND 65) and adult (PND 90) rats. Descendants of poly I:C treated rats showed significant increases of 15–18% in 5 H T 1 A R in the hippocampus (CA1) compared to controls at all developmental ages. Offspring of poly I:C treated rats exposed to HU210 during adolescence exhibited even greater elevations in 5 H T 1 A R (with increases of 44, 29, and 39% at PNDs 55, 65, and 90). No effect of HU210 alone was observed. Our results suggest a synergistic effect of prenatal infection and adolescent cannabinoid exposure on the integrity of the serotoninergic system in the hippocampus that may provide the neurochemical substrate for abnormal hippocampal-related functions relevant to schizophrenia. © 2012 Victoria S. Dalton et al.This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

A screening assay in the search of an alpha-synuclein PET radioligand

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A screening assay in the search of an alpha-synuclein PET radioligand

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A screening assay in the search of an alpha-synuclein PET radioligand

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Increased brain metabolism after acute administration of the synthetic cannabinoid HU210: A small animal PET imaging study with (18)F-FDG.

Cannabis use has been shown to alter brain metabolism in both rat models and humans although the observations between both species are conflicting. In the present study, we examined the short term effects of a single-dose injection of the synthetic cannabinoid agonist HU210 on glucose metabolism in the rat brain using small animal (18)F-2-fluoro-deoxyglucose (FDG) Positron Emission Tomography (PET) 15min (Day 1) and 24h (Day 2) post-injection of the agonist in the same animal. Young adult male Wistar rats received an intra-peritoneal injection of HU210 (100μg/kg, n=7) or vehicle (n=5) on Day 1. Approximately 1mCi of (18)F-FDG was injected intravenously into each animal at 15min (Day 1) and 24h (Day 2) post-injection of HU210. A 5-min Computer Tomography (CT) scan followed by a 20-min PET scan was performed 40min after each (18)F-FDG injection. Standardised Uptake Values (SUVs) were calculated for 10 brain regions of interest (ROIs). Global increased SUVs in the whole brain, hence global brain metabolism, were observed following HU210 treatment on Day 1 compared to the controls (21%, P<0.0001), but not in individual brain regions. On Day 2, however, no statistically significant differences were observed between the treated and control groups. At the 24h time point (Day 2), SUVs in the HU210 treated group returned to control levels (21-30% decrease compared to Day 1), in all ROIs investigated (P<0.0001). In the control group, SUVs did not differ between the two acquisition days in all brain regions. The present results suggest that high-dose HU210 increases brain glucose metabolism in the rat brain shortly after administration, in line with normalised human in vivo studies, an effect that was no longer apparent 24h later. Copyright © 2011 Elsevier Inc. All rights reserved