Anatomical Region Differences and Age-Related Changes in Copper, Zinc, and Manganese Levels in the Human Brain

Ramos, Patrícia; Santos, Agostinho; Pinto, Nair Rosas; Mendes, Ricardo; Magalhães, Teresa; Almeida, Agostinho

doi:10.1007/s12011-014-0093-6

Cited by 52 publications

(37 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Whether or how the previously reported decrease in serum Zn levels in AD 55 is associated with altered brain-Zn regulation is unclear. A previous study has suggested that HP may contain the highest Zn content among those brain-regions examined: 17 consistently, we found Zn levels to be higher in HP than other regions, although they approximated those in CB.…”

Section: Discussionsupporting

confidence: 82%

“…fresh or formalin-fixed), handling, numbers of samples, and intrinsic variation in the distribution of metals in the brain tissue, resulting perhaps from both compartmentalization and inter-regional differences. 7,16,17 Therefore, further mapping of the regional distribution of metals in the brain is required to substantiate and extend our understanding of the content of metals in various brain regions, and to associate these with region-specific variation in AD pathology. As one example, Cu, Fe and Zn are enriched in amyloid plaques from AD brain: 18,19 by contrast, measurement of levels of these metals in whole-brain tissue from affected regions has yielded somewhat inconsistent values.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Evidence for widespread, severe brain copper deficiency in Alzheimer's dementia

Church

Patassini

et al. 2017

Metallomics

View full text Add to dashboard Cite

Datasets comprising simultaneous measurements of many essential metals in Alzheimer's disease (AD) brain are sparse, and available studies are not entirely in agreement. To further elucidate this matter, we employed inductively-coupled-plasma mass spectrometry to measure post-mortem levels of 8 essential metals and selenium, in 7 brain regions from 9 cases with AD (neuropathological severity Braak IV-VI), and 13 controls who had normal ante-mortem mental function and no evidence of brain disease. Of the regions studied, three undergo severe neuronal damage in AD (hippocampus, entorhinal cortex and middle-temporal gyrus); three are less-severely affected (sensory cortex, motor cortex and cingulate gyrus); and one (cerebellum) is relatively spared. Metal concentrations in the controls differed among brain regions, and AD-associated perturbations in most metals occurred in only a few: regions more severely affected by neurodegeneration generally showed alterations in more metals, and cerebellum displayed a distinctive pattern. By contrast, copper levels were substantively decreased in all AD-brain regions, to 52.8-70.2% of corresponding control values, consistent with pan-cerebral copper deficiency. This copper deficiency could be pathogenic in AD, since levels are lowered to values approximating those in Menkes' disease, an X-linked recessive disorder where brain-copper deficiency is the accepted cause of severe brain damage. Our study reinforces others reporting deficient brain copper in AD, and indicates that interventions aimed at safely and effectively elevating brain copper could provide a new experimental-therapeutic approach.

show abstract

Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Evidence for widespread, severe brain copper deficiency in Alzheimer's dementia

Church

Patassini

et al. 2017

Metallomics

View full text Add to dashboard Cite

show abstract

“…3). This pattern was similar to that described for Cu in the human insular cortex (Dobrowolska et al 2008) and in agreement with previous reports indicating that Cu was more abundant in GM than WM in nonhuman primate brain (Bonilla et al 1984; Ramos et al 2014; Knauer et al 2017). Iron was observed in blood vessels, as expected due to its well-known association with hemoglobin, but also along layer IV and infragranular layers.…”

Section: Discussionsupporting

confidence: 92%

Molecular composition of the human primary visual cortex profiled by multimodal mass spectrometry imaging

et al. 2018

View full text Add to dashboard Cite

The primary visual cortex (area V1) is an extensively studied part of the cerebral cortex with well-characterized connectivity, cellular and molecular architecture and functions (for recent reviews see Amunts and Zilles, Neuron 88:1086–1107, 2015; Casagrande and Xu, Parallel visual pathways: a comparative perspective. The visual neurosciences, MIT Press, Cambridge, pp 494–506, 2004). In humans, V1 is defined by heavily myelinated fibers arriving from the radiatio optica that form the Gennari stripe in cortical layer IV, which is further subdivided into laminae IVa, IVb, IVcα and IVcβ. Due to this unique laminar pattern, V1 represents an excellent region to test whether multimodal mass spectrometric imaging could reveal novel biomolecular markers for a functionally relevant parcellation of the human cerebral cortex. Here we analyzed histological sections of three post-mortem brains with matrix-assisted laser desorption/ionization mass spectrometry imaging and laser ablation inductively coupled plasma mass spectrometry imaging to investigate the distribution of lipids, proteins and metals in human V1. We identified 71 peptides of 13 different proteins by in situ tandem mass spectrometry, of which 5 proteins show a differential laminar distribution pattern revealing the border between V1 and V2. High-accuracy mass measurements identified 123 lipid species, including glycerolipids, glycerophospholipids and sphingolipids, of which at least 20 showed differential distribution within V1 and V2. Specific lipids labeled not only myelinated layer IVb, but also IVa and especially IVc in a layer-specific manner, but also and clearly separated V1 from V2. Elemental imaging further showed a specific accumulation of copper in layer IV. In conclusion, multimodal mass spectrometry imaging identified novel biomolecular and elemental markers with specific laminar and inter-areal differences. We conclude that mass spectrometry imaging provides a promising new approach toward multimodal, molecule-based cortical parcellation.Electronic supplementary materialThe online version of this article (10.1007/s00429-018-1660-y) contains supplementary material, which is available to authorized users.

show abstract

“…In contrast, the increase in arginase activity after Mn-exposure in vivo is consistent with the increase of ARG2 protein; arginase is known to be stabilized in vitro by incorporation of Mn into each homomer [23]. Because the striatum exhibited more ARG2 than any other brain region, and because striatum normally accumulates Mn preferentially [14], the region may be especially vulnerable to Mn deficiency [24], though there is not a detectable difference in total striatal Mn levels between WT and YAC128Q at this stage [1]. The reduction in arginase enzyme activity in this HD model therefore suggests a specific cellular or subcellular deficit in Mn bioavailability for this enzyme.…”

Section: Discussionmentioning

confidence: 84%

Reduced bioavailable manganese causes striatal urea cycle pathology in Huntington's disease mouse model

Bichell

Węgrzynowicz

Tipps

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

Huntington’s disease (HD) is caused by a mutation in the huntingtin gene (HTT), resulting in profound striatal neurodegeneration through an unknown mechanism. Perturbations in the urea cycle have been reported in HD models and in HD patient blood and brain. In neurons, arginase is a central urea cycle enzyme, and the metal manganese (Mn) is an essential cofactor. Deficient biological responses to Mn, and reduced Mn accumulation have been observed in HD striatal mouse and cell models. Here we report in vivo and ex vivo evidence of a urea cycle metabolic phenotype in a prodromal HD mouse model. Further, either in vivo or in vitro Mn supplementation reverses the urea-cycle pathology by restoring arginase activity. We show that Arginase 2 (ARG2) is the arginase enzyme present in these mouse brain models, with ARG2 protein levels directly increased by Mn exposure. ARG2 protein is not reduced in the prodromal stage, though enzyme activity is reduced, indicating that altered Mn bioavailability as a cofactor leads to the deficient enzymatic activity. These data support a hypothesis that mutant HTT leads to a selective deficiency of neuronal Mn at an early disease stage, contributing to HD striatal urea-cycle pathophysiology through an effect on arginase activity.

show abstract

Anatomical Region Differences and Age-Related Changes in Copper, Zinc, and Manganese Levels in the Human Brain

Cited by 52 publications

References 51 publications

Evidence for widespread, severe brain copper deficiency in Alzheimer's dementia

Evidence for widespread, severe brain copper deficiency in Alzheimer's dementia

Molecular composition of the human primary visual cortex profiled by multimodal mass spectrometry imaging

Reduced bioavailable manganese causes striatal urea cycle pathology in Huntington's disease mouse model

Contact Info

Product

Resources

About