Neurotoxic, Redox-competent Alzheimer's β-Amyloid Is Released from Lipid Membrane by Methionine Oxidation

Barnham, Kevin J.; Ciccotosto, Giuseppe D.; Tickler, Anna K.; Ali, Feda E.; Smith, D.G.; Williamson, Nicholas A.; Lam, Yuen-Han; Carrington, Darryl; Tew, Deborah J.; Kocak, Gulcan; Volitakis, Irene; Separovic, Frances; Barrow, Colin J.; Wade, John D.; Masters, Colin L.; Cherny, Robert A.; Curtain, Cyril C.; Bush, Ashley I.; Cappai, Roberto

doi:10.1074/jbc.m305494200

Cited by 191 publications

(173 citation statements)

References 58 publications

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“…On the contrary, metal ions, such as copper, may react with met-35 to form a sulphuramyl free radical on the sulphur atom (one-electron oxidation), which causes enhanced oxidative stress via DNA/RNA and protein oxidation, lipid peroxidation and formation of reactive oxygen species, respectively (Butterfield, 2003). Moreover, the metal-dependent aggregation of Aβ is not affected by the formation of methionine sulphoxide (Barnham et al ., 2003) and met-35-oxidized Aβ comprises a major component of total brain Aβ in senile amyloid plaques (Atwood et al ., 2002; Dong et al ., 2003). Whilst met-35-oxidized Aβ is more hydrophilic, its enhanced release from the neuronal membrane into the synaptic cleft may mediate frequent contact with metal ions, such as zinc and copper, released during neural transmission (Barnham et al ., 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the metal-dependent aggregation of Aβ is not affected by the formation of methionine sulphoxide (Barnham et al ., 2003) and met-35-oxidized Aβ comprises a major component of total brain Aβ in senile amyloid plaques (Atwood et al ., 2002; Dong et al ., 2003). Whilst met-35-oxidized Aβ is more hydrophilic, its enhanced release from the neuronal membrane into the synaptic cleft may mediate frequent contact with metal ions, such as zinc and copper, released during neural transmission (Barnham et al ., 2003). This may contribute to metal-dependent aggregation and trigger Aβ precipitation as a kind of seed at a quite sensitive site of the neuron.…”

Section: Discussionmentioning

confidence: 99%

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CSF amyloid-β-peptides in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia

Bibl¹,

Mollenhauer²,

Esselmann³

et al. 2006

Brain

191

146

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As the differential diagnosis of dementias based on established clinical criteria is often difficult, biomarkers for applicable diagnostic testing are currently under intensive investigation. Amyloid plaques deposited in the brain of patients suffering from Alzheimer's disease, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) mainly consist of carboxy-terminally elongated forms of amyloid-beta (Aβ) peptides, such as Aβ1–42. Absolute Aβ1–42 levels in CSF have shown diagnostic value for the diagnosis of Alzheimer's disease, but the discrimination among Alzheimer's disease, DLB and PDD was poor. A recently established quantitative urea-based Aβ-sodium-dodecylsulphate–polyacrylamide-gel-electrophoresis with Western immunoblot (Aβ-SDS–PAGE/immunoblot) revealed a highly conserved Aβ peptide pattern of the carboxy-terminally truncated Aβ peptides 1–37, 1–38, 1–39 in addition to 1–40 and 1–42 in human CSF. We used the Aβ-SDS–PAGE/immunoblot to investigate the CSF of 23 patients with Alzheimer's disease, 21 with DLB, 21 with PDD and 23 non-demented disease controls (NDC) for disease-specific alterations of the Aβ peptide patterns in its absolute and relative quantities. The diagnostic groups were matched for age and severity of dementia. The present study is the first attempt to evaluate the meaning of Aβ peptide patterns in CSF for differential diagnosis of the three neurodegenerative diseases—Alzheimer's disease, DLB and PDD. The Aβ peptide patterns displayed disease-specific variations and the ratio of the differentially altered Aβ1–42 to the Aβ1–37 levels subsequently discriminated all diagnostic groups from each other at a highly significant level, except DLB from PDD. Additionally, a novel peptide with Aβ-like immunoreactivity was observed constantly in the CSF of all 88 investigated patients. The pronounced percentage increase of this peptide in DLB allowed a highly significant discrimination from PDD. Using a cut-off point of 0.954%, this marker yielded a diagnostic sensitivity and specificity of 81 and 71%, respectively. From several lines of indication, we consider this peptide to represent an oxidized α-helical form of Aβ1–40 (Aβ1–40*). The increased abundance of Aβ1–40* probably reflects a disease-specific alteration of the Aβ1–40 metabolism in DLB. We conclude that Aβ peptide patterns reflect disease-specific pathophysiological pathways of different dementia syndromes as distinct neurochemical phenotypes. Although Aβ peptide patterns failed to fulfil the requirements for a sole biomarker, their combined evaluation with other biomarkers is promising in neurochemical dementia diagnosis. It is noteworthy that DLB and PDD exhibit distinct clinical temporal courses, despite their similar neuropathological appearance. Their distinct molecular phenotypes support the view of different pathophysiological pathways for each of these neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CSF amyloid-β-peptides in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia

Bibl¹,

Mollenhauer²,

Esselmann³

et al. 2006

Brain

191

146

View full text Add to dashboard Cite

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“…H13A and H14A variants of Aβ42 were obtained from rPeptide, while Aβ 1-28 , Aβ [22][23][24][25][26][27][28][29][30][31][32][33][34][35] , α-MSH, and neurotensin were obtained from American Peptide. The Aβ42 mutant M35V (21) as well as Aβ42 with an oxidized methionine (M35 OX ) (20) were kindly provided by Dr. Kevin Barnham. Aβ proteins were either stored desiccated at −20 °C or dissolved in HFIP at 0.5 mg/mL at −20 °C.…”

Section: Methodsmentioning

confidence: 99%

“…by Aβ proteins mediates neurotoxicity (20)(21)(22), that merely altering membrane lipid composition protects PC12 cells from Aβ-mediated toxicity (23), and that plasma membranes from human brain are particularly effective at accelerating Aβ fibrillogenesis (24). Thus, it is important to understand the nature of the interaction between Aβ proteins and lipid membranes, particularly membranes subject to oxidative damage.…”

mentioning

confidence: 99%

Promotion of Oxidative Lipid Membrane Damage by Amyloid β Proteins

2005

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Senile plaques in the cerebral parenchyma are a pathognomonic feature of Alzheimer's disease (AD) and are mainly composed of aggregated fibrillar amyloid β (Aβ) proteins. The plaques are associated with neuronal degeneration, lipid membrane abnormalities, and chemical evidence of oxidative stress. The view that Aβ proteins cause these pathological changes has been challenged by suggestions that they have a protective function or that they are merely byproducts of the pathological process. This investigation was conducted to determine whether Aβ proteins promote or inhibit oxidative damage to lipid membranes. Using a mass spectrometric assay of oxidative lipid damage, the 42-residue form of Aβ (Aβ42) was found to accelerate the oxidative lipid damage caused by physiological concentrations of ascorbate and submicromolar concentrations of copper(II) ion. Under these conditions, Aβ42 was aggregated, but nonfibrillar. Ascorbate and copper produced H 2 O 2 , but Aβ42 reduced H 2 O 2 concentrations, and its ability to accelerate oxidative damage was not affected by catalase. Lipids could be oxidized by H 2 O 2 and copper-(II) in the absence of ascorbate, but only at significantly higher concentrations, and Aβ42 inhibited this reaction. These results indicate that the ability of Aβ42 to promote oxidative damage is more potent and more likely to be manifest in vivo than its ability to inhibit oxidative damage. In conjunction with prior results demonstrating that oxidatively damaged membranes cause Aβ42 to misfold and form fibrils, these results suggest a specific chemical mechanism linking Aβ42-promoted oxidative lipid damage to amyloid fibril formation.

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“…In the presence of amyloid copper undergoes redox cycling, which enhances the potential for copper induced toxicity in AD [164][165][166]. This is important because copper is increased in amyloid; however, copper levels are decreased in AD neuronal tissue [77], which could deprive copper-binding proteins such as superoxide dismutase and ceruloplasmin of the metal, which can impair their function.…”

Section: Coppermentioning

confidence: 99%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

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No disease modifying therapy exists for Alzheimer's disease (AD). The growing burden of this disease to our society necessitates continued investment in drug development. Over the last decade, multiple phase 3 clinical trials testing drugs that were designed to target established disease mechanisms of AD have all failed to benefit patients. There is, therefore, a need for new treatment strategies. Changes to the transition metals, zinc, copper, and iron, in AD impact on the molecular mechanisms of disease, and targeting these metals might be an alternative approach to treat the disease. Here we review how metals feature in molecular mechanisms of AD, and we describe preclinical and clinical data that demonstrate the potential for metal-based drug therapy.

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Neurotoxic, Redox-competent Alzheimer's β-Amyloid Is Released from Lipid Membrane by Methionine Oxidation

Cited by 191 publications

References 58 publications

CSF amyloid-β-peptides in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia

CSF amyloid-β-peptides in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia

Promotion of Oxidative Lipid Membrane Damage by Amyloid β Proteins

Biometals and Their Therapeutic Implications in Alzheimer's Disease

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