Enhanced G‐protein activation by a mixture of Aβ(25–35), Aβ(1–40/42) and zinc

Molnár, Zs-S.; Kovacs, Patrick; Laczkó, Ilona; Soós, Katalin; Fülöp, Lívia; Penke, Botond; Lengyel, Imre

doi:10.1111/j.1471-4159.2004.02427.x

Cited by 6 publications

(6 citation statements)

References 73 publications

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“…Further, treatment of AD patients with clioquinol reduced the level of circulating A␤, in addition to the effects on plasma zinc and cognitive performance, mentioned above. In addition to its promotion of the aggregation of A␤, zinc also markedly increased G protein activation mediated by soluble A␤ in cultured cortical membranes (47). Therefore, the abnormalities of zinc metabolism in brain arising from dysregulation of gene expression may create a predisposition to pathological conditions such as AD.…”

Section: Discussionmentioning

confidence: 99%

Perinatal ω-3 polyunsaturated fatty acid supply modifies brain zinc homeostasis during adulthood

Jayasooriya

Ackland

Mathai

et al. 2005

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

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Dietary ω-3 polyunsaturated fatty acid (PUFA) influences the expression of a number of genes in the brain. Zinc transporter (ZnT) 3 has been identified as a putative transporter of zinc into synaptic vesicles of neurons and is found in brain areas such as hippocampus and cortex. Neuronal zinc is involved in the formation of amyloid plaques, a major characteristic of Alzheimer's disease. The present study evaluated the influence of dietary ω-3 PUFA on the expression of the ZnT3 gene in the brains of adult male Sprague-Dawley rats. The rats were raised and/or maintained on a control (CON) diet that contained ω-3 PUFA or a diet deficient (DEF) in ω-3 PUFA. ZnT3 gene expression was analyzed by using real-time PCR, free zinc in brain tissue was determined by zinquin staining, and total zinc concentrations in plasma and cerebrospinal fluid were determined by atomic absorption spectrophotometry. Compared with CON-raised animals, DEF-raised animals had increased expression of ZnT3 in the brain that was associated with an increased level of free zinc in the hippocampus. In addition, compared with CON-raised animals, DEF-raised animals had decreased plasma zinc level. No difference in cerebrospinal fluid zinc level was observed. The results suggest that overexpression of ZnT3 due to a perinatal ω-3 PUFA deficiency caused abnormal zinc metabolism in the brain. Conceivably, the influence of dietary ω-3 PUFA on brain zinc metabolism could explain the observation made in population studies that the consumption of fish is associated with a reduced risk of dementia and Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Perinatal ω-3 polyunsaturated fatty acid supply modifies brain zinc homeostasis during adulthood

Jayasooriya

Ackland

Mathai

et al. 2005

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

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“…Studies of levels of G proteins in AD brain show that the proteins tend to be preserved (41)(42)(43) although function tends to be impaired with progression of the disease (43)(44)(45). Recent studies of Molna´r et al (46) show that Aß [25][26][27][28][29][30][31][32][33][34][35] and Aß 1-40 caused a concentration-dependent increase in GTP binding. Our observation of elevated guanine nucleotide binding protein may represent a response of Aß-treated cells to accommodate increased GTP binding.…”

Section: Discussionmentioning

confidence: 94%

Quantitative Proteomic Analysis of Mitochondria from Primary Neuron Cultures Treated with Amyloid Beta Peptide

et al. 2005

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Increasing evidence supports a role for altered mitochondrial function in the pathogenesis of neuron degeneration in Alzheimer's disease (AD). Although several studies have examined the effect of amyloid beta peptide (Abeta), on activities of individual proteins in primary neuron cultures, there have been no studies of the effects of Abeta on the mitochondrial proteome. Here, we quantitatively measured changes in mitochondrial proteins of primary rat cortical neuron cultures exposed to 25 microM Abeta(25-35) for 16 h using isotope coded affinity tag (ICAT) labeling and 2-dimensional liquid chromatography/tandem mass spectrometry (2D-LC/MS/MS) which allows simultaneous identification and quantification of cysteine-containing proteins. The analysis of enriched mitochondrial fractions identified 10 proteins including sodium/potassium-transporting ATPase, cofilin, dihydropyrimidinase, pyruvate kinase and voltage dependent anion channel 1 that were statistically significantly (P < 0.05) altered in Abeta-treated cultures. Elevations of proteins associated with energy production suggest that cells undergoing Abeta-mediated apoptosis increase synthesis of proteins essential for ATP production and efflux in an attempt to maintain metabolic function.

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“…In fact, N‐truncated Aβ(1–42) fragments, which, similarly to Aβ(25–35), lack the histidine/tyrosine residues for copper binding, may originate in vivo (Saido et al, 1996; Eckman et al, 2001). These, including Aβ(17–42) (Saido et al, 1996) and Aβ(20–40) (Eckman et al, 2001), might all bind copper via their N‐terminus group, become toxic, and function as catalysts that promote Aβ(1–42) toxicity in AD brain (Molnár et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Aβ(25–35) and its C‐ and/or N‐blocked derivatives: Copper driven structural features and neurotoxicity

Giuffrida

Grasso²,

Ruvo³

et al. 2006

J of Neuroscience Research

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The toxic properties of beta-amyloid protein, Abeta(1-42), the major component of senile plaques in Alzheimer's disease, depend on nucleation-dependent oligomerization and aggregation. In addition, Abeta(1-42) toxicity is favored by the presence of trace metals, which affect the secondary structure of the peptide. A peptide comprising 11 residues within Abeta(1-42) [Abeta(25-35)] aggregates and retains the neurotoxic activity of Abeta(1-42). We have used both Abeta(25-35) and its C-amidated or N-acetylated/C-amidated derivatives to investigate the role of copper(II) in modulating the conformation and aggregation state as well as the neurotoxic properties of amyloid peptides. Electrospray ionization mass spectrometry (ESI-MS) and electron paramagnetic resonance (EPR) measurements were performed to verify the formation of copper(II)/Abeta(25-35) complexes and to determine the coordination mode, respectively. Abeta(25-35) and its derivatives were analyzed by circular dichroism spectroscopy to assess their secondary structure, subjected to thioflavine-T (Th-T) binding assay to reveal beta-sheet structured aggregates formation, and imaged by scanning force microscopy. Toxicity was assessed on mature cultures of rat cortical neurons. We found that beta-sheet-structured species of Abeta(25-35) were neurotoxic, whereas the random-coil-structured derivatives were devoid of effect. Interestingly, copper promoted the random-coil/beta-sheet transition of Abeta(25-35), with ensuing peptide toxicity, but it induced the toxicity of the N-acetylated/C-amidated derivative without affecting peptide folding. Moreover, copper did not influence either the folding or the activity of the C-amidated Abeta(25-35), suggesting that blockade of the C-terminus of Abeta peptides might be sufficient to prevent Abeta toxicity.

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Enhanced G‐protein activation by a mixture of Aβ(25–35), Aβ(1–40/42) and zinc

Cited by 6 publications

References 73 publications

Perinatal ω-3 polyunsaturated fatty acid supply modifies brain zinc homeostasis during adulthood

Perinatal ω-3 polyunsaturated fatty acid supply modifies brain zinc homeostasis during adulthood

Quantitative Proteomic Analysis of Mitochondria from Primary Neuron Cultures Treated with Amyloid Beta Peptide

Aβ(25–35) and its C‐ and/or N‐blocked derivatives: Copper driven structural features and neurotoxicity

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