Cerebrospinal fluid trace element content in dementia

Hershey, Charles O.; Hershey, Linda A.; Varnes, Arthur W.; Vibhakar, Shardul D.; Lavin, Patrick; Strain, William H.

doi:10.1212/wnl.33.10.1350

Cited by 119 publications

(66 citation statements)

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“…While free Cu(II) does not exist in the cytosol (34), extracellular Cu(II) may be more readily exchangeable (24). Cu(II) interaction with A␤ may be exaggerated in AD where copper levels are abnormally elevated in the neuropil (7,36), cerebrospinal fluid (37,38), and especially in amyloid where the concentration of copper has been measured at 30 g/g (Ϸ0.5 mM, dry weight) (7). Extraction of copper may be the basis of our recent discovery that copper-selective chelators, such as bathocuproine, facilitate the solubilization of A␤ from deposits in post-mortem AD brain specimens (8).…”

Section: Discussionmentioning

confidence: 99%

Cu(II) Potentiation of Alzheimer Aβ Neurotoxicity

Huang¹,

Cuajungco²,

Atwood³

et al. 1999

Journal of Biological Chemistry

723

383

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Oxidative stress markers as well as high concentrations of copper are found in the vicinity of A␤ amyloid deposits in Alzheimer's disease. The neurotoxicity of A␤ in cell culture has been linked to H 2 O 2 generation by an unknown mechanism. We now report that Cu(II) markedly potentiates the neurotoxicity exhibited by A␤ in cell culture. The potentiation of toxicity is greatest for A␤1-42 > A␤1-40 > > mouse/rat A␤1-40, corresponding to their relative capacities to reduce Cu(II) to Cu(I), form H 2 O 2 in cell-free assays and to exhibit amyloid pathology. The copper complex of A␤1-42 has a highly positive formal reduction potential (Ϸ؉500 -550 mV versus Ag/AgCl) characteristic of strongly reducing cuproproteins. These findings suggest that certain redox active metal ions may be important in exacerbating and perhaps facilitating A␤-mediated oxidative damage in Alzheimer's disease.Oxidative damage in the neocortex coincides with A␤ accumulation both in Alzheimer's disease (AD) 1 (1) and in A␤ amyloid-bearing transgenic mice (2), but the mechanisms of oxidation are unknown. The possibility that A␤ accumulation causes oxidation, perhaps by radical formation (3), has been explored, but the nature of the chemistry involved in generating A␤-associated oxidation products such as lipid peroxides (4) remains to be elaborated. In culture, A␤-induced neurotoxicity is characterized by elevated cellular H 2 O 2 and is combated by antioxidants such as vitamin E and catalase (5). The origin of the toxic H 2 O 2 is unknown.Recently, we reported that Fe(III) interacts directly with A␤1-42 and A␤1-40 to produce H 2 O 2 and TBARS formation in a cell-free manner in vitro, through reduction of the metal ion (6), suggesting that a source of the H 2 O 2 that mediates toxicity in cell cultures exposed to A␤ is extracellular. Cu(II)and Fe(III) have been found in abnormally high concentrations in amyloid plaques (Ϸ0.4 and Ϸ1 mM, respectively) and AD-affected neuropil (7), and copper-selective chelators have been shown to dissolve A␤ deposits extracted from AD post-mortem brain specimens (8). Therefore, these metal ions may be important cofactors in A␤-associated oxidative damage. Importantly, we have also reported that the generation of both Cu(II) and Fe(III)-mediated TBARS is greatest for A␤1-42 Ͼ A␤1-40 Ͼ Ͼ rat A␤1-40 (6). This rank order is of interest because it mirrors the relative participation of the peptides in amyloid neuropathology, and because the most active one (A␤1-42) is overproduced in familial AD (9). Rats and mice do not develop amyloid (10), even in mice transgenic for familial-AD linked mutant presenilin that overexpress endogenous mouse A␤1-42 (11), probably due to the three amino acid substitutions in their homologue of A␤ (Arg 5 3 Gly, Tyr 10 3 Phe, and His 13 3 Arg) (12).Although Fe(III) mediates and potentiates A␤1-40 toxicity in cell culture (13), it is not clear whether this is due to metal interaction with the peptide or due to a nonspecific increase in reactive oxygen species (ROS) generation within the cell. R...

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Section: Discussionmentioning

confidence: 99%

Cu(II) Potentiation of Alzheimer Aβ Neurotoxicity

Huang¹,

Cuajungco²,

Atwood³

et al. 1999

Journal of Biological Chemistry

723

383

View full text Add to dashboard Cite

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“…[y32P]2N3ATP (specific activity, [5][6][7][8][9][10][11][12][13][14] mCi/,tmol) was then prepared and purified as described for ['t-32P]8N3ATP. Protein molecular size standards were from Bio-Rad.…”

Section: Methodsmentioning

confidence: 99%

“…Amyloid, paired helical filament, and a1-antichymotrypsin immunoreactivity have been reported to be elevated in the CSF of AD patients (4)(5)(6). The CSF has also been examined for concentration changes in neuropeptides (7), biogenic amines and their metabolites (8), amino acid or amino acid derivatives (9), vitamins (10), and trace elements (11). However, none of these compounds has emerged as a reliable marker for AD.…”

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confidence: 99%

Detection of glutamine synthetase in the cerebrospinal fluid of Alzheimer diseased patients: a potential diagnostic biochemical marker.

Gunnersen

Haley²

1992

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

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“…It is reported that zinc concentration in CSF is in the range 150-380 nM. [32][33][34] If it is the same as zinc concentration in the brain extracellular fluid, a large portion of zinc is not free ion in the brain extracellular fluid under the basal (static) condition. At zincergic synapses such as Shaffer collateral and mossy fiber synapses, extracellular Zn 2+ levels are dynamically modified by the degree of activity-dependent Zn 2+ release, which is required for learning and memory via synaptic plasticity as described below.…”

Section: +mentioning

confidence: 99%

Is Vulnerability of the Dentate Gyrus to Aging and Amyloid-β<sub>1–42</sub> Neurotoxicity Linked with Modified Extracellular Zn<sup>2+</sup> Dynamics?

Takeda

Tamano

2018

Biological & Pharmaceutical Bulletin

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The basal levels of extracellular Zn 2 are in the range of low nanomolar concentrations in the hippocampus and perhaps increase age-dependently. Extracellular Zn 2 dynamics is critical for cognitive activity and excess influx of extracellular Zn 2 into hippocampal neurons is a known cause of cognitive decline. The dentate gyrus is vulnerable to aging in the hippocampus and affected in the early stage of Alzheimer's disease (AD). The reasons remain unclear. Neurogenesis-related apoptosis may induce non-specific neuronal depolarization by efflux of intracellular K in the dentate gyrus and be markedly increased along with aging. Extracellular Zn 2 influx into dentate granule cells via high K -induced perforant pathway excitation leads to cognitive decline. Modified extracellular Zn 2 dynamics in the dentate gyrus of aged rats is linked with vulnerability to cognitive decline. Amyloid-β 1-42 (Aβ 1-42 ) is a causative candidate for AD pathogenesis. When Aβ 1-42 concentration reaches picomolar in the extracellular compartment in the dentate gyrus, Zn-Aβ 1-42 is formed in the extracellular compartment and rapidly taken up into dentate granule cells, followed by Aβ 1-42 -induced cognitive decline that is due to Zn 2 released from Aβ 1-42 , suggesting that dentate granule cells are sensitive to extracellular Zn 2 -dependent Aβ 1-42 toxicity. This paper deals with proposed vulnerability of the dentate gyrus to aging and Aβ 1-42 neurotoxicity.

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Cerebrospinal fluid trace element content in dementia

Cited by 119 publications

References 0 publications

Cu(II) Potentiation of Alzheimer Aβ Neurotoxicity

Cu(II) Potentiation of Alzheimer Aβ Neurotoxicity

Detection of glutamine synthetase in the cerebrospinal fluid of Alzheimer diseased patients: a potential diagnostic biochemical marker.

Is Vulnerability of the Dentate Gyrus to Aging and Amyloid-β<sub>1–42</sub> Neurotoxicity Linked with Modified Extracellular Zn<sup>2+</sup> Dynamics?

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