Zinc and copper modulate Alzheimer Aβ levels in human cerebrospinal fluid

Strozyk, Dorothea; Launer, Lenore J.; Adlard, Paul A.; Cherny, Robert A.; Tsatsanis, Andrew; Volitakis, Irene; Blennow, Kaj; Petrovitch, Helen; White, Lon R.; Bush, Ashley I.

doi:10.1016/j.neurobiolaging.2007.10.012

Cited by 137 publications

(94 citation statements)

References 42 publications

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“…Recently, it has been demonstrated that CSF Cu levels negatively correlate with Ab42 levels in AD patients (elevated Cu and decreased Ab42) (Strozyk et al 2007). In good agreement with this report, we found that Cu treatment apparently had a small effect on Ab42 levels.…”

Section: Discussionsupporting

confidence: 92%

Effect of copper intake on CSF parameters in patients with mild Alzheimer’s disease: a pilot phase 2 clinical trial

Kessler

Pajonk²,

Bach

et al. 2008

J Neural Transm

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A plethora of reports suggest that copper (Cu) homeostasis is disturbed in Alzheimer's disease (AD). In the present report we evaluated the efficacy of oral Cu supplementation on CSF biomarkers for AD. In a prospective, randomized, double-blind, placebo-controlled phase 2 clinical trial (12 months long) patients with mild AD received either Cu-(II)-orotate-dihydrate (verum group; 8 mg Cu daily) or placebo (placebo group). The primary outcome measures in CSF were Ab42, Tau and Phospho-Tau. The clinical trial demonstrates that longterm oral intake of 8 mg Cu can be excluded as a risk factor for AD based on CSF biomarker analysis. Cu intake had no effect on the progression of Tau and Phospho-Tau levels in CSF. While Ab42 levels declined by 30% in the placebo group (P = 0.001), they decreased only by 10% (P = 0.04) in the verum group. Since decreased CSF Ab42 is a diagnostic marker for AD, this observation may indicate that Cu treatment had a positive effect on a relevant AD biomarker. Using mini-mental state examination (MMSE) and Alzheimer disease assessment scale-cognitive subscale (ADAS-cog) we have previously demonstrated that there are no Cu treatment effects on cognitive performance, however. Finally, CSF Ab42 levels declined significantly in both groups within 12 months supporting the notion that CSF Ab42 may be valid not only for diagnostic but also for prognostic purposes in AD.

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Section: Discussionsupporting

confidence: 92%

Effect of copper intake on CSF parameters in patients with mild Alzheimer’s disease: a pilot phase 2 clinical trial

Kessler

Pajonk²,

Bach

et al. 2008

J Neural Transm

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“…25 A hint towards this interpretation comes from our estimation-via a clearance measure-that about 3% of serum 'free' copper crosses the BBB in living patients and possibly interact with Aβ. 15 The latter finding was recently confirmed by other authors, who demonstrated an interaction between copper and Aβ in the CSF, 26 probably resulting in catalytic generation of peroxides (H 2 O 2 ) and Aβ aggregation, 15,26 ultimately leading to neurodegeneration. 27 Alternative hypotheses could be put forward to explain ceruloplasmin fragmentation in AD.…”

Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 65%

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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“…Our current data indicate that lipid rafts provide a favorable environment for the co-enrichment of copper and A␤, especially under conditions of copper deficiency. We hypothesize that in aging and AD, where there is intracellular copper deficiency (5,6,69), the concomitant enrichment of A␤ and copper within lipid rafts promotes the formation of redoxactive A␤⅐Cu 2ϩ complexes, fostering the catalytic oxidation of cholesterol, lipid, and the generation of neurotoxic H 2 O 2 . This further creates a vulnerable environment for A␤ to cross-link, forming SDS-resistant oligomers characteristic of A␤ extracted from AD brains (67,68).…”

Section: Discussionmentioning

confidence: 99%

Paradoxical Condensation of Copper with Elevated β-Amyloid in Lipid Rafts under Cellular Copper Deficiency Conditions

Hung¹,

Robb²,

Volitakis

et al. 2009

Journal of Biological Chemistry

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Redox-active copper is implicated in the pathogenesis of Alzheimer disease (AD), ␤-amyloid peptide (A␤) aggregation, and amyloid formation. A␤⅐copper complexes have been identified in AD and catalytically oxidize cholesterol and lipid to generate H 2 O 2 and lipid peroxides. The site and mechanism of this abnormality is not known. Growing evidence suggests that amyloidogenic processing of the ␤-amyloid precursor protein (APP) occurs in lipid rafts, membrane microdomains enriched in cholesterol. ␤-and ␥-secretases, and A␤ have been identified in lipid rafts in cultured cells, human and rodent brains, but the role of copper in lipid raft amyloidogenic processing is presently unknown. In this study, we found that copper modulates flotillin-2 association with cholesterol-rich lipid raft domains, and consequently A␤ synthesis is attenuated via copper-mediated inhibition of APP endocytosis. We also found that total cellular copper is associated inversely with lipid raft copper levels, so that under intracellular copper deficiency conditions, A␤⅐copper complexes are more likely to form. This explains the paradoxical hypermetallation of A␤ with copper under tissue copper deficiency conditions in AD.Imbalance of metal ions has been recognized as one of the key factors in the pathogenesis of Alzheimer disease (AD).2 Aberrant interactions between copper or zinc with the ␤-amyloid peptide (A␤) released into the glutamatergic synaptic cleft vicinity could result in the formation of toxic A␤ oligomers and aggregation into plaques characteristic of AD brains (reviewed in Ref. 1). Copper, iron, and zinc are highly concentrated in extracellular plaques (2, 3), and yet brain tissues from AD (4 -6) and human ␤-amyloid precursor protein (APP) transgenic mice (7-10) are paradoxically copper deficient compared with agematched controls. Elevation of intracellular copper levels by genetic, dietary, and pharmacological manipulations in both AD transgenic animal and cell culture models is able to attenuate A␤ production (7,9,(11)(12)(13)(14)(15). However, the underlying mechanism is at present unclear.Abnormal cholesterol metabolism is also a contributing factor in the pathogenesis of AD. Hypercholesterolemia increases the risk of developing AD-like pathology in a transgenic mouse model (16). Epidemiological and animal model studies show that a hypercholesterolemic diet is associated with A␤ accumulation and accelerated cognitive decline, both of which are further aggravated by high dietary copper (17, 18). In contrast, biochemical depletion of cholesterol using statins, inhibitors of 3-hydroxy-3-methyglutaryl coenzyme A reductase, and methyl-␤-cyclodextrin, a cholesterol sequestering agent, inhibit A␤ production in animal and cell culture models (19 -25).Cholesterol is enriched in lipid rafts, membrane microdomains implicated in A␤ generation from APP cleavage by ␤-and ␥-secretases. Recruitment of BACE1 (␤-secretase) into lipid rafts increases the production of sAPP ␤ and A␤ (23, 26). The ␤-secretase-cleaved APP C-terminal fragment (␤-C...

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Zinc and copper modulate Alzheimer Aβ levels in human cerebrospinal fluid

Cited by 137 publications

References 42 publications

Effect of copper intake on CSF parameters in patients with mild Alzheimer’s disease: a pilot phase 2 clinical trial

Effect of copper intake on CSF parameters in patients with mild Alzheimer’s disease: a pilot phase 2 clinical trial

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

Paradoxical Condensation of Copper with Elevated β-Amyloid in Lipid Rafts under Cellular Copper Deficiency Conditions

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