The βA4 amyloid precursor protein binding to copper

Hesse, Lars; Beher, Dirk; Masters, Colin L.; Multhaup, Gerd

doi:10.1016/0014-5793(94)00658-x

Cited by 242 publications

(205 citation statements)

References 32 publications

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“…The interaction between H202 and Cu can potentially result in generation of the highly toxic OH' (Gunther et al, 1995): Cu (I) + H z 0 2 + Cu (11) + OH' + OH- (1) Cu may have a central role in several neurodegenerative disorders, including AD, CJD, and ALS. High levels of Cu have been detected in AD-associated plaques (Love11 et al, 1998) and can interact with both amyloid-/3 (AP) (Atwood et al, 1998;Bondy et al, 1998; A.I.B., unpublished observations) and amyloid precursor protein (APP) (Hesse et al, 1994;Multhaup et al, 1996Multhaup et al, , 1998. These interactions could result in the generation of toxic free radicals and subsequent neuronal dysfunction or death (Bondy et al, 1998;Multhaup et al, 1998).…”

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confidence: 99%

Exacerbation of Copper Toxicity in Primary Neuronal Cultures Depleted of Cellular Glutathione

White

Bush

Beyreuther

et al. 1999

Journal of Neurochemistry

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Perturbations to glutathione (GSH) metabolism may play an important role in neurodegenerative disorders such as Alzheimer's, Parkinson's, and prion diseases. A primary function of GSH is to prevent the toxic interaction between free radicals and reactive transition metals such as copper (Cu). Due to the potential role of Cu in neurodegeneration, we examined the effect of GSH depletion on Cu toxicity in murine primary neuronal cultures. Depletion of cellular GSH with L-buthionine-[S,R]-sulfoximine resulted in a dramatic potentiation of Cu toxicity in neurons without effect on iron (Fe) toxicity. Similarly, inhibition of glutathione reductase (GR) activity with 1,3-bis(2-chloroethyl)-l -nitrosurea also increased Cu toxicity in neurons. To determine if the Alzheimer's amyloid-p (Ap) peptide can affect neuronal resistance to transition metal toxicity, we exposed cultures to nontoxic concentrations of Ap25-35 in the presence or absence of Cu or Fe. Ap25-35 pretreatment was found to deplete neuronal GSH and increase GR activity, confirming the ability of Ap to perturb neuronal GSH homeostasis.Ap25-35 pretreatment potently increased Cu toxicity but had no effect on Fe toxicity. These studies demonstrate an important role for neuronal GSH homeostasis in selective protection against Cu toxicity, a finding with widespread implications for neurodegenerative disorders.

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confidence: 99%

Exacerbation of Copper Toxicity in Primary Neuronal Cultures Depleted of Cellular Glutathione

White

Bush

Beyreuther

et al. 1999

Journal of Neurochemistry

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“…APP is synthesised as a membrane-located and secreted protein. It binds Cu and can reduce Cu 2þ to Cu þ (Hesse et al, 1994;Multhaup, 1997;Multhaup et al, 1996). The protein is transported from the cell to the axonal membrane and to the dendritic plasma membrane and could, thus, transport Cu þ along this way (Simons et al, 1995).…”

Section: Neurodegenerative Diseasesmentioning

confidence: 99%

Hohenheim Consensus Workshop: Copper

Schümann¹,

Classen

Dieter

et al. 2002

Eur J Clin Nutr

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Copper (Cu) is an essential trace element with many physiological functions. Homeostatic mechanisms exist to allow Cu to act as a cofactor in enzymatic processes and to prevent accumulation of Cu to toxic levels. The aim of this commentary is to better understand the role of dietary Cu supply in deficiency and under physiological and pathological conditions. The essentiality of Cu can be attributed to its role as a cofactor in a number of enzymes that are involved in the defence against oxidative stress. Cu, however, has a second face, that of a toxic compound as it is observed with accumulating evidence in hepatic, neurodegenerative and cardiovascular diseases. The destructive potential of Cu can be attributed to inherent physico-chemical properties.The main property is its ability to take part in Fenton-like reactions in which the highly reactive and extremely deleterious hydroxyl radical is formed. Diseases caused by dietary Cu overload could be based on a genetic predisposition. Thus, an assessment of risk-groups, such as infants with impaired mechanisms of Cu homeostasis regarding detoxification, is of special interest, as their Cu intake with resuspended formula milk may be very high. This implies the need for reliable diagnostic markers to determine the Cu status. These topics were introduced at the workshop by the participants followed by extensive group discussion. The consensus statements were agreed on by all members. One of the conclusions is that a re-assessment of published data is necessary and future research is required.

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“…APP695 was isolated from rat brain as described previously [17]. Radio-iodination of purified rat brain APP was done with the IodoBeads iodination reagent (Pierce).…”

Section: Purification and Radioiodination Of Appmentioning

confidence: 99%

“…The secreted or membrane-associated forms of APP have also been shown to be involved in cell growth regulation, to regulate neurite length and to participate in neuronal cell and cell-matrix adhesion [12][13][14]. The ability of APP to stimulate cell adhesion and growth does not depend on the presence of the KPI domain and may derive from its high affinities for heparin, heparin sulfate proteoglycans [15], laminin and collagen type IV [16][17][18][19][20]. A growth-promoting activity on A-1 fibroblasts has been mapped to residues 328-332 of the APP695 isoform which lacks the KPI domain [21].…”

Section: Introductionmentioning

confidence: 99%

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Interaction between the zinc(II) and the heparin binding site of the Alzheimer's disease βA4 amyloid precursor protein (APP)

et al. 1994

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The Alzheimer's disease flA4 amyloid precursor protein (APP) has been suggested to be involved in regulation of cell growth, neurite outgrowth and adhesiveness through binding to beparin sulfate proteoglycans. In order to unravel the molecular mechanisms underlying those functions in vitro we show that APP binds in a time dependent and saturable manner to the glycosaminoglycan side-chains of proteoglycans but not to chondroitinsulfate. We also demonstrate an interaction between the high affinity beparin binding site within the carbohydrate domain of APP and the zinc(II) binding site of APP. We show that the affinity for beparin is increased two-to four-fold in the presence of micromolar zinc(II). Thus micromolar concentrations of zinc(II) appear to be able to modulate the binding of APP to heparin side-chains of proteoglycans and as shown previously [Science 265 (1994[Science 265 ( ) 1464[Science 265 ( -1467 to induce the aggregation of soluble amyloid flA4 protein.

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The βA4 amyloid precursor protein binding to copper

Cited by 242 publications

References 32 publications

Exacerbation of Copper Toxicity in Primary Neuronal Cultures Depleted of Cellular Glutathione

Exacerbation of Copper Toxicity in Primary Neuronal Cultures Depleted of Cellular Glutathione

Hohenheim Consensus Workshop: Copper

Interaction between the zinc(II) and the heparin binding site of the Alzheimer's disease βA4 amyloid precursor protein (APP)

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