Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer's disease: possible relation to oxidative stress

Deibel, Michael; Ehmann, W. D.; Markesbery, William R.

doi:10.1016/s0022-510x(96)00203-1

Cited by 503 publications

(372 citation statements)

References 42 publications

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“…Zinc also activates many kinases (including protein kinases A and C, calmodulin-dependent kinase, ribosomal S6 protein kinase, and Erk (55-62)) and may contribute to neuronal death due to transient global ischemia or traumatic brain injury (82)(83)(84)(85)(86). Increased zinc concentrations (Ͼ300 M) have been found in AD brains (87)(88)(89) and in the serum of AD patients with an APOE ⑀4 allele (90). These findings are consistent with a synergistic role of zinc and apoE4 in AD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Increased tau Phosphorylation in Apolipoprotein E4 Transgenic Mice Is Associated with Activation of Extracellular Signal-regulated Kinase

Harris

Brecht

et al. 2004

Journal of Biological Chemistry

144

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Although apolipoprotein (apo) E4 is present in amyloid plaques and neurofibrillary tangles, its pathogenic role in Alzheimer's disease (AD) is unclear. Neuronal expression of apoE4 or apoE4 fragments in transgenic mice increases tau phosphorylation. To identify the kinase responsible for the increase, we studied transgenic mice expressing human apoE3 or apoE4 in neurons under the control of the neuron-specific enolase promoter. Brain levels of phosphorylated tau (p-tau) and phosphorylated (active) extracellular signal-regulated kinase (pErk) increased with age in both groups but were considerably higher in the apoE4 mice. Other candidate kinases, including glycogen synthase kinase 3␤ and cyclin-dependent kinase-5 and its activators p25 and p35, were not significantly altered. The increases in p-Erk and p-tau were highest in the hippocampus, intermediate in the cortex, and lowest in the cerebellum. In the hippocampus, p-Erk and p-tau accumulated in the hilus and CA3 region of the dentate gyrus, where high levels of zinc are found along mossy fibers. In Neuro-2a cells stably expressing apoE3 or apoE4, treatment with ZnCl 2 generated 2-fold more p-Erk and 3-fold more p-tau in the apoE4-expressing cells. Phosphorylation of Erk and tau was reduced by preincubation with the Erk pathway inhibitor U0126. Thus, increased tau phosphorylation in apoE4 transgenic mice was associated with Erk activation and could be modified by zinc, suggesting that apoE4 and zinc act in concert to contribute to the pathogenesis of AD.Human apolipoprotein (apo) 1 E4 has been identified as a major risk factor for Alzheimer's disease (AD) (1, 2). It increases the occurrence and lowers the age of onset of AD and is associated with ϳ40 -65% of cases of sporadic and familial AD (1, 2). The neuropathological hallmarks of AD are neuritic amyloid plaques and neurofibrillary tangles (NFTs) in the brain (3-5). The plaques are extracellular deposits consisting primarily of amyloid-beta (A␤) peptides (3-5), the proteolytic products of the amyloid protein precursor. NFTs are primarily intracellular deposits composed largely of highly phosphorylated tau (p-tau), a microtubule-associated protein (4), as well as phosphorylated neurofilaments of high molecular weight (6, 7). Both plaques and NFTs contain apoE (8 -10), but the role of apoE in the pathogenesis of these lesions is unclear.Several hypotheses have been proposed to explain the association of apoE4 with AD (10 -14). They include modulation of the deposition and clearance of A␤ peptides and the formation of plaques (15-21), impairment of the antioxidative defense system (22), dysregulation of neuronal signaling pathways (23), altered phosphorylation of tau and NFT formation (24 -29), depletion of cytosolic androgen receptor levels in the brain (30, 31), potentiation of A␤-induced lysosomal leakage and apoptosis in neuronal cells (32), and promotion of endosomal abnormalities linked to A␤ overproduction (33-35). However, the mechanisms of these apoE4-mediated detrimental effects are largely unknown, ...

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Section: Discussionmentioning

confidence: 99%

Increased tau Phosphorylation in Apolipoprotein E4 Transgenic Mice Is Associated with Activation of Extracellular Signal-regulated Kinase

Harris

Brecht

et al. 2004

Journal of Biological Chemistry

144

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“…Bulk tissue analysis of the postmortem AD brain has generated inconsistent changes between AD and controls [73][74][75][76][77], which might reflect different anatomic areas examined and different sample preparations (e.g., tissue fixation affects zinc measurement [78]). But analysis of bulk tissue zinc content is likely to miss the most interesting changes to zinc in the AD brain.…”

Section: Zincmentioning

confidence: 99%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

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No disease modifying therapy exists for Alzheimer's disease (AD). The growing burden of this disease to our society necessitates continued investment in drug development. Over the last decade, multiple phase 3 clinical trials testing drugs that were designed to target established disease mechanisms of AD have all failed to benefit patients. There is, therefore, a need for new treatment strategies. Changes to the transition metals, zinc, copper, and iron, in AD impact on the molecular mechanisms of disease, and targeting these metals might be an alternative approach to treat the disease. Here we review how metals feature in molecular mechanisms of AD, and we describe preclinical and clinical data that demonstrate the potential for metal-based drug therapy.

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“…Transition metals are one of the most important factors that produce the reactive oxygen species, and they are implicated in the generation of ROS in various neurodegenerative diseases (Youdim et al, 1993;Deibel et al, 1996). These transition metals mediate the formation of the hydroxyl radical through the iron-catalyzed or copper-catalyzed HaberWeiss reactions (Haber and Weiss, 1934).…”

Section: Production Of Reactive Oxygen Species By Transition Metalsmentioning

confidence: 99%

Cellular and Molecular Pathways of Ischemic Neuronal Death

Won¹,

Kim²,

Gwag³

2002

BMB Reports

201

172

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Three routes have been identified triggering neuronal death under physiological and pathological conditions. Excess activation of ionotropic glutamate receptors cause influx and accumulation of Ca 2+ and Na + that result in rapid swelling and subsequent neuronal death within a few hours. The second route is caused by oxidative stress due to accumulation of reactive oxygen and nitrogen species. Apoptosis or programmed cell death that often occurs during developmental process has been coined as additional route to pathological neuronal death in the mature nervous system. Evidence is being accumulated that excitotoxicity, oxidative stress, and apoptosis propagate through distinctive and mutually exclusive signal transduction pathway and contribute to neuronal loss following hypoxic-ischemic brain injury. Thus, the therapeutic intervention of hypoxic-ischemic neuronal injury should be aimed to prevent excitotoxicity, oxidative stress, and apoptosis in a concerted way.

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Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer's disease: possible relation to oxidative stress

Cited by 503 publications

References 42 publications

Increased tau Phosphorylation in Apolipoprotein E4 Transgenic Mice Is Associated with Activation of Extracellular Signal-regulated Kinase

Increased tau Phosphorylation in Apolipoprotein E4 Transgenic Mice Is Associated with Activation of Extracellular Signal-regulated Kinase

Biometals and Their Therapeutic Implications in Alzheimer's Disease

Cellular and Molecular Pathways of Ischemic Neuronal Death

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