Increased regional brain concentrations of ceruloplasmin in neurodegenerative disorders

Loeffler, David A.; LeWitt, Peter A.; Juneau, Paul; Sima, A. A. F.; Nguyen, Huu Phuc; DeMaggio, A. J.; Brickman, Chaim M.; Brewer, George J.; Dick, Robert; Troyer, Matthew D.; Kanaley, Lisa

doi:10.1016/s0006-8993(96)00782-2

Cited by 209 publications

(135 citation statements)

References 60 publications

Supporting

Mentioning

123

Contrasting

Unclassified

Order By: Relevance

“…No correlation was found between copper content and copper͞zinc-SOD content in LC and SN, although this enzyme contains 25% of the total copper content of the brain. The conditions of copper decrease and Cp increase, found in LC of aged subjects, resemble that reported in SN of PD patients (15,42,44). Thus, copper could eventually be more involved than iron in neurodegenerative processes of LC.…”

Section: Cp In Lc Increases In Aging To Compensate For Copper Decreassupporting

confidence: 74%

The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging

Zecca

Stroppolo

Gatti

et al. 2004

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

423

469

View full text Add to dashboard Cite

In this study, a comparative analysis of metal-related neuronal vulnerability was performed in two brainstem nuclei, the locus coeruleus (LC) and substantia nigra (SN), known targets of the etiological noxae in Parkinson's disease and related disorders. LC and SN pars compacta neurons both degenerate in Parkinson's disease and other Parkinsonisms; however, LC neurons are comparatively less affected and with a variable degree of involvement. In this study, iron, copper, and their major molecular forms like ferritins, ceruloplasmin, neuromelanin (NM), manganese-superoxide dismutase (SOD), and copper͞zinc-SOD were measured in LC and SN of normal subjects at different ages. Iron content in LC was much lower than that in SN, and the ratio heavy-chain ferritin͞iron in LC was higher than in the SN. The NM concentration was similar in LC and SN, but the iron content in NM of LC was much lower than SN. In both regions, heavy-and light-chain ferritins were present only in glia and were not detectable in neurons. These data suggest that in LC neurons, the iron mobilization and toxicity is lower than that in SN and is efficiently buffered by NM. The bigger damage occurring in SN could be related to the higher content of iron. Ferritins accomplish the same function of buffering iron in glial cells. Ceruloplasmin levels were similar in LC and SN, but copper was higher in LC. However, the copper content in NM of LC was higher than that of SN, indicating a higher copper mobilization in LC neurons. Manganese-SOD and copper͞zinc-SOD had similar age trend in LC and SN. These results may explain at least one of the reasons underlying lower vulnerability of LC compared to SN in Parkinsonian syndromes. L ocus coeruleus (LC) is the main brain region containing norepinephrine neurons. The rostral projections from these neurons seem to be involved in the modulation of neuronal activity, metabolism, and memory (1, 2), whereas the spinal cord projections are known to modulate spinal motoneuron function (3, 4).Neuronal loss in LC occurs in conditions such as Parkinson's disease (PD) and Alzheimer's disease and Down's syndrome (5, 6) with different cellular loss in rostral and caudal parts of LC. In Alzheimer's disease and Down's syndrome, it is not clear whether neuronal loss in LC is a primary event or a consequence of retrograde degeneration of cortically projecting cells due to the loss of cortical synapses. In idiopathic PD, most studies have documented a higher degree of neuronal loss in substantia nigra (SN) compared to LC (5-8). However, a recent study reported extensive impairment of LC neurons in PD (9). SN and LC share anatomical and biochemical similarities, being both pigmented because of neuromelanin (NM), and both composed of catecholaminergic neurons. Yet, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridineintoxicated subjects, LC neurons are spared, whereas a large neuronal depletion occurs in SN (10, 11). Also, in other types of Parkinsonian syndromes caused by exposure to toxins, the LC neurons seem less damaged than those of...

show abstract

Section: Cp In Lc Increases In Aging To Compensate For Copper Decreassupporting

confidence: 74%

The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging

Zecca

Stroppolo

Gatti

et al. 2004

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

423

469

View full text Add to dashboard Cite

show abstract

“…The decrease in copper and increase in manganese in the brains of APP and C100 Tg mice mirrors changes in the AD brain, which has also been reported to have decreased levels of copper relative to age-matched controls (7,8,10,11), and increased levels of manganese (11). Brain coppper concentration is related to plasma copper concentration (51), and both plasma (52,53) and CSF (54) copper levels are significantly elevated in AD.…”

Section: Discussionmentioning

confidence: 81%

Overexpression of Alzheimer's Disease Amyloid-β Opposes the Age-dependent Elevations of Brain Copper and Iron

Maynard¹,

Cappai²,

Volitakis³

et al. 2002

Journal of Biological Chemistry

335

308

View full text Add to dashboard Cite

“…Postmortem Cu levels in CNS of AD patients were found decreased (Deibel et al 1996) or unchanged (Loeffler et al 1996). Controversial results have also been published on the level of Cu in plasma and brain in AD patients.…”

Section: Discussionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

Increased regional brain concentrations of ceruloplasmin in neurodegenerative disorders

Cited by 209 publications

References 60 publications

The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging

The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging

Overexpression of Alzheimer's Disease Amyloid-β Opposes the Age-dependent Elevations of Brain Copper and Iron

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

Contact Info

Product

Resources

About