Serum zinc, copper, insulin and lipids in Alzheimer's disease epsilon 4 apolipoprotein E allele carriers*

González, Marcos; [], Martin; Cacho,; Breñas,; Arroyo, Vicente; García‐Berrocal,; Navajo,; González‐Buitrago,

doi:10.1046/j.1365-2362.1999.00471.x

Cited by 112 publications

(81 citation statements)

References 39 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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“…However, in some cases (e.g. patients carrying ApoE e4 alleles) AD may be associated with increased circulating zinc levels (Gonzalez et al 1999). A variety of socioeconomic factors contribute to insufficient micronutrient intake in the elderly population.…”

Section: Risk Of Zinc Deficiency In the Elderlymentioning

confidence: 99%

“…For example, elevated plasma zinc is an independent risk factor for AD among e4 carriers (Gonzalez et al 1999) and the risk of AD is greater among DM2 patients that also carry the e4 allele (Peila et al 2002). Suggesting that ApoE e4 disrupts zinc homeostasis, mice expressing human e4 have decreased tissue MT levels compared to mice expressing e3 (Graeser et al 2012).…”

Section: Zinc and Insulin Signaling In Diabetes Mellitus And Dementiamentioning

confidence: 99%

“…However, the mechanism through which ApoE affects zinc homeostasis is largely unknown. Decreased tissue MT could potentially explain the increased circulating levels of zinc (Gonzalez et al 1999). However, the total level of zinc in the mouse liver was not effected by ApoE genotype (Graeser et al 2012).…”

Section: Zinc and Insulin Signaling In Diabetes Mellitus And Dementiamentioning

confidence: 99%

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Zinc and the aging brain

Nuttall

Oteiza

2013

Genes Nutr

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Alterations in trace element homeostasis could be involved in the pathology of dementia, and in particular of Alzheimer's disease (AD). Zinc is a structural or functional component of many proteins, being involved in numerous and relevant physiological functions. Zinc homeostasis is affected in the elderly, and current evidence points to alterations in the cellular and systemic distribution of zinc in AD. Although the association of zinc and other metals with AD pathology remains unclear, therapeutic approaches designed to restore trace element homeostasis are being tested in clinical trials. Not only could zinc supplementation potentially benefit individuals with AD, but zinc supplementation also improves glycemic control in the elderly suffering from diabetes mellitus. However, the findings that select genetic polymorphisms may alter an individual's zinc intake requirements should be taken into consideration when planning zinc supplementation. This review will focus on current knowledge regarding pathological and protective mechanisms involving brain zinc in AD to highlight areas where future research may enable development of new and improved therapies.

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“…There is new evidence suggesting that brain copper may redistribute outside the neuronal cell, leaving it relatively deficient. 7 Although past studies in man have found no differences between AD and controls in serum copper levels, [8][9][10][11] more sophisticated measurements have recently shown both an increase, [12][13][14][15] and a decrease of these levels, 16,17 thus opening a debate on a toxic or protective role of copper in AD. Results from our laboratory, though, suggest that it is the ceruloplasmin-copper relationship, rather than the level of absolute (i.e., bound and not bound to ceruloplasmin) serum copper, that may be the key issue in interpreting in vivo copper findings in AD.…”

Section: Introductionmentioning

confidence: 99%

Ceruloplasmin fragmentation is implicated in 'free' copper deregulation of Alzheimer disease

Squitti

Quattrocchi

Salustri³

et al. 2008

Prion

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A dysfunction in copper homeostasis seems to occur in Alzheimer's disease (AD). We recently demonstrated that an excess of non-ceruloplasmin-copper (i.e., 'free' copper) correlates with the main functional and anatomical deficits as well as the cerebrospinal markers of the disease, thus suggesting that copper contributes to AD neurodegeneration. Aim of this study was to investigate the profile of serum ceruloplasmin isoforms immunoreactive protein in relation to copper dysfunction in AD. Twenty-five AD patients and 25 controls were included in the study. All subjects underwent individual measurements of serum ceruloplasmin and copper concentrations, and the amount of 'free' copper was computed for each copper and ceruloplasmin pair. Serum samples were also pooled and analyzed by two dimensional polyacrylamide gel electrophoresis (2-D PAGE) and western blot analysis. The mean concentration of 'free' copper resulted higher in AD patients than in controls. Ceruloplasmin 2-D PAGE western blot analysis of pooled sera showed in the AD samples low-molecular-weight spots in the <50 kDa range that were not detected in controls' pooled sera (p < 0.029).Our data indicate a ceruloplasmin fragmentation in the serum of AD patients, possibly related to 'free' copper deregulation in this disease.

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Serum zinc, copper, insulin and lipids in Alzheimer's disease epsilon 4 apolipoprotein E allele carriers*

Abstract: In AD we have found a significant association between higher serum Zn, Cu and insulin concentrations and the presence of an epsilon 4 apoE allele, but only greater serum Zn concentration appears to be an independent risk factor associated with the development of AD.

Cited by 112 publications

References 39 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

Zinc and the aging brain

Ceruloplasmin fragmentation is implicated in 'free' copper deregulation of Alzheimer disease

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