A metabolomic study of the CRND8 transgenic mouse model of Alzheimer's disease

Department of Biochemistry, The Hopkins Building, Tennis Court Road, University of Cambridge, Cambridge CB21QW, UK.
Neurochemistry International (Impact Factor: 3.09). 07/2010; 56(8):937-47. DOI: 10.1016/j.neuint.2010.04.001
Source: PubMed


Alzheimer's disease is the most common neurodegenerative disease of the central nervous system characterized by a progressive loss in memory and deterioration of cognitive functions. In this study the transgenic mouse TgCRND8, which encodes a mutant form of the amyloid precursor protein 695 with both the Swedish and Indiana mutations and develops extracellular amyloid beta-peptide deposits as early as 2-3 months, was investigated. Extract from eight brain regions (cortex, frontal cortex, cerebellum, hippocampus, olfactory bulb, pons, midbrain and striatum) were studied using (1)H NMR spectroscopy. Analysis of the NMR spectra discriminated control from APP695 tissues in hippocampus, cortex, frontal cortex, midbrain and cerebellum, with hippocampal and cortical region being most affected. The analysis of the corresponding loading plots for these brain regions indicated a decrease in N-acetyl-L-aspartate, glutamate, glutamine, taurine (exception hippocampus), gamma-amino butyric acid, choline and phosphocholine (combined resonances), creatine, phosphocreatine and succinate in hippocampus, cortex, frontal cortex (exception gamma-amino butyric acid) and midbrain of affected animals. An increase in lactate, aspartate, glycine (except in midbrain) and other amino acids including alanine (exception frontal cortex), leucine, iso-leucine, valine and water soluble free fatty acids (0.8-0.9 and 1.2-1.3 ppm) were observed in the TgCRND8 mice. Our findings demonstrate that the perturbations in metabolism are more widespread and include the cerebellum and midbrain. Furthermore, metabolic perturbations are associated with a wide range of metabolites which could improve the diagnosis and monitoring of the progression of Alzheimer's disease.

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Available from: Reza Salek
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    • "These selected ages correspond to pre-plaque, plaque burden, overt AD-like pathology and advanced AD-like pathology stage, respectively [34]. The cortex and hippocampus were compared because they are the most affected regions in Tg mice [35], whereas the cerebellum was chosen as a relatively spared control region. Overall, our data suggest that among the vulnerable brain regions, AIF is involved in AD-associated PCD in the cortex but not in the hippocampus. "
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    ABSTRACT: Background Recent evidence has suggested that Alzheimer’s disease (AD)-associated neuronal loss may occur via the caspase-independent route of programmed cell death (PCD) in addition to caspase-dependent mechanisms. However, the brain region specificity of caspase-independent PCD in AD-associated neurodegeneration is unknown. We therefore used the transgenic CRND8 (TgCRND8) AD mouse model to explore whether the apoptosis inducing factor (AIF), a key mediator of caspase-independent PCD, contributes to cell loss in selected brain regions in the course of aging. Results Increased expression of truncated AIF (tAIF), which is directly responsible for cell death induction, was observed at both 4- and 6-months of age in the cortex. Concomitant with the up-regulation of tAIF was an increase in the nuclear translocation of this protein. Heightened tAIF expression or translocation was not observed in the hippocampus or cerebellum, which were used as AD-vulnerable and relatively AD-spared regions, respectively. The cortical alterations in tAIF levels were accompanied by increased Bax expression and mitochondrial translocation. This effect was preceded by a significant reduction in ATP content and an increase in reactive oxygen species (ROS) production, detectable at 2 months of age despite negligible amounts of amyloid-beta peptides (Aβ). Conclusions Taken together, these data suggest that AIF is likely to play a region-specific role in AD-related caspase-independent PCD, which is consistent with aging-associated mitochondrial impairment and oxidative stress.
    Full-text · Article · Jun 2014 · BMC Neuroscience
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    • "Other MRS studies have confirmed alterations in brain levels of NAA and glutamate but in other mouse models: PS2APP mice (von Kienlin et al. 2005) and APP-PS1 mice (Marjanska et al. (2005). Brain extracts from TgCRND8 mice were examined by 1 H- NMR (Salek et al. 2010) and similar alterations in NAA and glutamate were found, but other metabolite disturbances such as taurine, γ-amino butyric acid (GABA), choline, phosphocholine, creatine, phosphocreatine and succinate were also observed. Brain tissue derived from the APP-PS1 mouse model has been examined by metabolomics techniques involving both GC-MS (Trushina et al. 2012) and 1 H-NMR (Graham et al. 2013a). "
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    ABSTRACT: Brain tissue from so-called Alzheimer’s disease (AD) mouse models has previously been examined using 1H NMR-metabolomics, but comparable information concerning human AD is negligible. Since no animal model recapitulates all the features of human AD we undertook the first 1H NMR-metabolomics investigation of human AD brain tissue. Human post-mortem tissue from 15 AD subjects and 15 age-matched controls was prepared for analysis through a series of lyophilised, milling, extraction and randomisation steps and samples were analysed using 1H NMR. Using partial least squares discriminant analysis, a model was built using data obtained from brain extracts. Analysis of brain extracts led to the elucidation of 24 metabolites. Significant elevations in brain alanine (15.4 %) and taurine (18.9 %) were observed in AD patients (p ≤ 0.05). Pathway topology analysis implicated either dysregulation of taurine and hypotaurine metabolism or alanine, aspartate and glutamate metabolism. Furthermore, screening of metabolites for AD biomarkers demonstrated that individual metabolites weakly discriminated cases of AD [receiver operating characteristic (ROC) AUC <0.67; p < 0.05]. However, paired metabolites ratios (e.g. alanine/carnitine) were more powerful discriminating tools (ROC AUC = 0.76; p < 0.01). This study further demonstrates the potential of metabolomics for elucidating the underlying biochemistry and to help identify AD in patients attending the memory clinic.
    Full-text · Article · Nov 2013 · Metabolomics
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    • "The metabolites responsible for the separation were different at 2.5 months when no amyloid plaques were present compared to older ages. A more recent publication described a very interesting 1 H NMR metabolomic study of seven brain regions from young (2–3 months) and old (12–13 months) CRND8 transgenic mice [11]. This model expresses a double mutant form of human A␤PP and develops amyloid plaques at the early stages of the disease, between 2 and 3 months. "
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    ABSTRACT: In the quest for biomarkers of onset and progression of Alzheimer's disease, a 1H NMR-based metabolomic study was performed on the simple single-transgenic Tg2576 mouse model. These mice develop a slow cognitive decline starting by 6 months and express amyloid plaques from 10 months of age. The metabolic profiles of extracts from five brain regions (frontal cortex, rhinal cortex, hippocampus, midbrain, and cerebellum) of Tg2576 male mice were compared to those of controls, at 1, 3, 6 and 11 months of age. The most obvious differences were due to brain regions. Age was also a discriminating parameter. Metabolic perturbations were already detected in the hippocampus and the rhinal cortex of transgenic mice as early as 1 month of age with decreased concentrations of glutamate (Glu) and N-acetylaspartate (NAA) compared to those in wild-type animals. Metabolic changes were more numerous in the hippocampus and the rhinal cortex of 3 month-old transgenic mice and involved Glu, NAA, myo-inositol, creatine, phosphocholine, and γ-aminobutyric acid (only in the hippocampus) whose concentrations decreased. A metabolic disruption characterized by an increase in the hippocampal concentrations of Glu, creatine, and taurine was detected in 6 month-old transgenic mice. At this time point, the chemical profile of the cerebellum was slightly affected. At 11 months, all the brain regions analyzed (except the frontal cortex) were metabolically altered, with mainly a marked increase in the formation of the neuroprotective metabolites creatine and taurine. Our findings demonstrate that metabolic modifications occur long before the onset of behavioral impairment.
    Full-text · Article · Oct 2013 · Journal of Alzheimer's disease: JAD
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