Metabonomic alterations in hippocampus, temporal and prefrontal cortex with age in rats

Zhang, Xianrong; Liu, Huilang; Wu, Junfang; Zhang, Xu; Liu, Maili; Wang, Yong

doi:10.1016/j.neuint.2009.02.004

Cited by 66 publications

(50 citation statements)

References 47 publications

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“…In the frontal cortex, the level of glutamate, glutamine, NAA, taurine and tCr decreased. Thus, we show that hippocampus and frontal cortex may have fluctuating metabolite levels with time, as previously demonstrated using brain extracts (Zhang et al 2009;Paban et al 2010).…”

Section: Changes Observed In Healthy Animalssupporting

confidence: 84%

Altered neurochemical profile in the McGill‐R‐Thy1‐APP rat model of Alzheimer's disease: a longitudinal in vivo¹H MRS study

Nilsen

Melø

Sæther

et al. 2012

Journal of Neurochemistry

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We investigated metabolite levels during the progression of pathology in McGill-R-Thy1-APP rats, a transgenic animal model of Alzheimer's disease, and in healthy age-matched controls. Rats were subjected to in vivo 1 H magnetic resonance spectroscopy (MRS) of the dorsal hippocampus at age 3, 9 and 12 months and of frontal cortex at 9 and 12 months. At 3 months, a stage in which only Ab oligomers are present, lower glutamate, myo-inositol and total choline content were apparent in McGill-R-Thy1-APP rats. At age 9 months, lower levels of glutamate, GABA, N-acetylaspartate and total choline and elevated myo-inositol and taurine were found in dorsal hippocampus, whereas lower levels of glutamate, GABA, glutamine and N-acetylaspartate were found in frontal cortex.At age 12 months, only the taurine level was significantly different in dorsal hippocampus, whereas taurine, myo-inositol, N-acetylaspartate and total creatine levels were significantly higher in frontal cortex. McGill-R-Thy1-APP rats did not show the same changes in metabolite levels with age as displayed in the controls, and overall, prominent and complex metabolite differences were evident in this transgenic rat model of Alzheimer's disease. The findings also demonstrate that in vivo 1 H MRS is a powerful tool to investigate diseaserelated metabolite changes in the brain. Keywords: biomarkers, GABA, glutamate, metabolism, N-acetylaspartate, transgenic rats. Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia in the elderly. It is characterized by accumulation of extracellular plaques containing aggregated amyloid b (Ab) peptides and intracellular neurofibrillary tangles composed of hyperphosphorylated tau proteins. In addition, regional loss of neurons and synapses, progressive cognitive decline and regional hypometabolism occurs (Mosconi 2005; SerranoPozo et al. 2011). Emerging evidence also suggest that, intraneuronal Ab oligomers may contribute substantially to AD disease progression (Haass and Selkoe 2007).There is no definite biomarker for the diagnosis of AD, which motivates the search for neuroimaging markers that may facilitate early detection of the disease. Using 1 H magnetic resonance spectroscopy (MRS), the regional concentration of low-molecular-weight metabolites can be measured non-invasively and provides insight into neurochemical processes of normal and pathological conditions in vivo. Performing 1 H MRS of patients with AD has revealed a consistent pattern of decreased levels of Nacetylaspartate (NAA) or NAA/total creatine (tCr) and increased myo-inositol (mIns) or mIns/tCr (Kantarci et al. 2003;Shiino et al. 2012). NAA is synthesised in neurons (Wiame et al. 2010) Abbreviations used: AD, Alzheimer's disease; APP, amyloid precursor protein; Ab, amyloid beta; CMR glc , cerebral metabolic rate of glucose; CRLB, Cramer-Rao lower bounds; DH, dorsal hippocampus; FCX, frontal cortex; GS, glutamine synthetase; mIns, myo-inositol; MRI, magnetic resonance imaging; MRS, magnetic resona...

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Section: Changes Observed In Healthy Animalssupporting

confidence: 84%

Altered neurochemical profile in the McGill‐R‐Thy1‐APP rat model of Alzheimer's disease: a longitudinal in vivo¹H MRS study

Nilsen

Melø

Sæther

et al. 2012

Journal of Neurochemistry

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“…When healthy aging in humans was recently accessed with combined 13 C-/ 1 H-MRS, an association was found between reduced neuronal mitochondrial metabolism and altered glial mitochondrial metabolism in aged (76 ± 8 y) participants (49). Another study found that lactate levels measured by 1 H-NMR in 88-to 96-wk-old rats were significantly increased (50). In contrast, longlived Ames dwarf mice have decreased plasma lactate levels (51).…”

Section: Discussionmentioning

confidence: 99%

High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio

Ross

Öberg

Brené

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

241

171

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At present, there are few means to track symptomatic stages of CNS aging. Thus, although metabolic changes are implicated in mtDNA mutation-driven aging, the manifestations remain unclear. Here, we used normally aging and prematurely aging mtDNA mutator mice to establish a molecular link between mitochondrial dysfunction and abnormal metabolism in the aging process. Using proton magnetic resonance spectroscopy and HPLC, we found that brain lactate levels were increased twofold in both normally and prematurely aging mice during aging. To correlate the striking increase in lactate with tissue pathology, we investigated the respiratory chain enzymes and detected mitochondrial failure in key brain areas from both normally and prematurely aging mice. We used in situ hybridization to show that increased brain lactate levels were caused by a shift in transcriptional activities of the lactate dehydrogenases to promote pyruvate to lactate conversion. Separation of the five tetrameric lactate dehydrogenase (LDH) isoenzymes revealed an increase of those dominated by the Ldh-A product and a decrease of those rich in the Ldh-B product, which, in turn, increases pyruvate to lactate conversion. Spectrophotometric assays measuring LDH activity from the pyruvate and lactate sides of the reaction showed a higher pyruvate → lactate activity in the brain. We argue for the use of lactate proton magnetic resonance spectroscopy as a noninvasive strategy for monitoring this hallmark of the aging process. The mtDNA mutator mouse allows us to conclude that the increased LDH-A/LDH-B ratio causes high brain lactate levels, which, in turn, are predictive of aging phenotypes.mtDNA mutator mouse | proton magnetic resonance spectroscopy | in situ hybridization | COX/SDH enzyme histochemistry | HPLC

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“…One hypothesis holds that dysfunction of the blood-brain barrier, which limits iron entry to the brain via highly regulated transport systems, might play a role in brain iron overload. [19][20][21] Another hypothesis with strong experimental support proposes that brain iron accumulation is a consequence of the dysregulation of proteins that govern cellular iron homeostasis. Mammalian cellular iron efflux is mediated by the sole iron exporter ferroportin 1 (Fpn1), a transmembrane protein.…”

Section: Introductionmentioning

confidence: 99%

Calorie Restriction Down-Regulates Expression of the Iron Regulatory Hormone Hepcidin in Normal and d-Galactose–Induced Aging Mouse Brain

Wei

Shi²,

Li³

et al. 2014

Rejuvenation Research

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It has been shown that iron progressively accumulates in the brain with age. Calorie restriction (CR) may allay many of the adverse effects of aging on the brain, yet the underlying mechanisms, in particular in relation to brain iron metabolism, remain unclear. This study aimed to investigate the role of CR in the regulation of cerebral cellular iron homeostasis. C57BL/6 mice were randomly divided into four groups of eight. The control group was fed a conventional diet ad libitum; the CR group received 70% of the calories of the control mouse intake per day; the d-galactose (d-gal) group received subcutaneous injection of d-gal at a dose of 100 mg/kg once daily to produce mouse model of aging; the d-gal plus CR group received both of the two interventions for 14 weeks. The Morris water maze (MWM) was employed to test the cognitive performance of all animals, and the expression of iron regulatory genes, ferroportin and hepcidin, in the cortex and hippocampus were detected by quantitative real-time PCR. Compared to the controls, the d-gal group mice showed significant spatial reference memory deficits in the MWM test, whereas the d-gal-CR group mice exhibited almost normal cognitive function, indicating that CR protects against d-gal-induced learning and memory impairment. Hepcidin mRNA expression was increased in the d-gal group, decreased in the CR group, and was basically unchanged in the d-gal-CR group. There was no statistical difference in the transmembrane iron exporter ferroportin expression between control and any of the experimental groups. The results suggest that the antiaging effects of CR might partially lie in its capacity to reduce or avoid age-related iron accumulation in the brain through down-regulating expression of brain hepcidin-the key negative regulator for intracellular iron efflux-and that facilitating the balance of brain iron metabolism may be a promising anti-aging measure.

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Metabonomic alterations in hippocampus, temporal and prefrontal cortex with age in rats

Cited by 66 publications

References 47 publications

Altered neurochemical profile in the McGill‐R‐Thy1‐APP rat model of Alzheimer's disease: a longitudinal in vivo¹H MRS study

Altered neurochemical profile in the McGill‐R‐Thy1‐APP rat model of Alzheimer's disease: a longitudinal in vivo¹H MRS study

High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio

Calorie Restriction Down-Regulates Expression of the Iron Regulatory Hormone Hepcidin in Normal and d-Galactose–Induced Aging Mouse Brain

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Metabonomic alterations in hippocampus, temporal and prefrontal cortex with age in rats

Cited by 66 publications

References 47 publications

Altered neurochemical profile in the McGill‐R‐Thy1‐APP rat model of Alzheimer's disease: a longitudinal in vivo1H MRS study

Altered neurochemical profile in the McGill‐R‐Thy1‐APP rat model of Alzheimer's disease: a longitudinal in vivo1H MRS study

High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio

Calorie Restriction Down-Regulates Expression of the Iron Regulatory Hormone Hepcidin in Normal and d-Galactose–Induced Aging Mouse Brain

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Product

Resources

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Altered neurochemical profile in the McGill‐R‐Thy1‐APP rat model of Alzheimer's disease: a longitudinal in vivo¹H MRS study

Altered neurochemical profile in the McGill‐R‐Thy1‐APP rat model of Alzheimer's disease: a longitudinal in vivo¹H MRS study