Elevation of serum copper levels discriminates Alzheimer’s disease from vascular dementia

Squitti, Rosanna; Pasqualetti, Patrizio; Cassetta, Emanuele; Forno, Gloria Dal; Cesaretti, S.; Pedace, F.; Finazzi‐Agrò, Alessandro; Rossini, Paolo Maria

doi:10.1212/01.wnl.0000068013.27968.29

Cited by 50 publications

(27 citation statements)

References 7 publications

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“…Plasma Cu levels being within the normal range (65-165 lg/dl) in AD patients are in good agreement with an earlier study (Jeandel et al 1989). However, other studies suggest that elevated Cu levels might be a risk factor for AD without providing a rationale (Squitti et al 2002(Squitti et al , 2003(Squitti et al , 2004. These results are in contrast to the present study, which might be explained by the fact that we studied Cu levels in the same patients within a 12 months period and can therefore better control for inter-individual differences.…”

Section: Discussionsupporting

confidence: 90%

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: 90%

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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“…Our current findings are not in concurrence with the previous reports. Studies done by Squitti et al (12) shows raised serum copper levels in AD as compared to VaD. The raised serum copper seen in AD and VaD in the present study may signify that raised copper in AD is due to disturbed copper metabolism but secondary to oxidative stress seen as part of neurodegeneration occurring in AD and VaD.…”

Section: Discussionsupporting

confidence: 65%

“…In vivo studies demonstrate that elevated serum copper levels differentiate patients with AD from age matched normal individuals with good selectivity and specificity (12). According to the above studies serum copper concentration may be a potential marker for AD.…”

Section: Introductionmentioning

confidence: 83%

Serum copper in Alzheimer’s disease and vascular dementia

Agarwal

Kushwaha

Tripathi

et al. 2008

Indian J Clin Biochem

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“…6C) (n ϭ 7) (p Ͻ 0.0001). There is no reported difference in serum iron (76) and ferritin (77) noted in AD blood and iron level. Thus, a simple blood-based biomarker for AD has yet to show promise to complement the use of clinical assessment with MRI imaging.…”

Section: Discussionmentioning

confidence: 95%

Selective Translational Control of the Alzheimer Amyloid Precursor Protein Transcript by Iron Regulatory Protein-1

Cho

Cahill

Vanderburg

et al. 2010

Journal of Biological Chemistry

156

190

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Iron influx increases the translation of the Alzheimer amyloid precursor protein (APP) via an iron-responsive element (IRE)RNA Alzheimer disease (AD)3 is a neurodegenerative process that is the leading cause of death worldwide for people over the age of 65 (1, 2). The pathological hallmarks of AD in the brain cortex are not only abundant extracellular amyloid plaques (3) and intracellular tangles of the neurofibrillary protein tau but also increased brain iron (in ferritin-associated plaques) (4).The major component of these plaques is the 40 -42-amino acid ␤-amyloid (A␤) peptide cleaved from the amyloid precursor protein (APP) (5), which is the ubiquitously expressed trans-membrane metalloprotein (6). ␤-Secretase and ␥-secretases generate the 40 -42-amino acid A␤ peptide that is toxic to brain neurons, an event that is accelerated in the presence of iron (7-11). Intracellular iron levels control APP translation via iron-responsive 5Ј-untranslated region (APP 5Ј-UTR) sequences in the APP transcript (1, 12), likely mediated via internal ribosome entry mechanisms (13).In mammalian cells, iron homeostasis is regulated by posttranscriptional events by iron regulatory proteins (IRP1 and IRP2) that bind at high affinity to iron-responsive element (IRE) RNA hairpins and repress the translation of the iron storage protein ferritin as well as transcripts of other iron-associated proteins (14 -16). During conditions of iron influx, both IRP1 and IRP2 are released from the light (L) and heavy (H) ferritin IREs to increase the translational efficiency of the L-and H-chains of this intracellular iron storage multimer (17,18). Transferrin receptor (TfR) mRNA stability is controlled by five IREs (19,20) in its 3Ј-UTR, which binds IRP2 more avidly than IRP1 and thereby stabilizes TfR mRNA in a low intracellular iron milieu. Emerging evidence clearly supports iron directly interacting with the L-and H-ferritin IREs to weaken equal binding of IRP1-IRP2 (21).The canonical IRE stem loops encoded by L-and H-ferritin and TfR mRNAs are highly conserved throughout evolution. Similar 5Ј-UTR-specific IREs control the translation of Hif-2␣ (22), ferroportin (IREG-1) (23), the erythroid heme biosynthetic aminolevulinate synthase (eALAS) (24), and mitochondrial aconitase (25), each of which bind avidly to IRP1 to a greater degree than IRP2. In contrast to TfR mRNA, which binds at high affinity to IRP2, the duodenal divalent metal ion transporter (DMT1) (26) encodes an IRE stem loop immediately downstream from its stop codon and preferentially binds * This work was supported, in whole or in part, by National Institutes of Health Grant AG20181 (to J. T. R.). This work was also supported by a Zenith award from the Alzheimer's Association (to J. T. R.

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Elevation of serum copper levels discriminates Alzheimer’s disease from vascular dementia

Cited by 50 publications

References 7 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

Serum copper in Alzheimer’s disease and vascular dementia

Selective Translational Control of the Alzheimer Amyloid Precursor Protein Transcript by Iron Regulatory Protein-1

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