Metalloenzyme-like Activity of Alzheimer's Disease β-Amyloid

Opazo, Carlos; Huang, Xudong; Cherny, Robert A.; Moir, Robert D.; Roher, Alex E.; White, Anthony R.; Cappai, Roberto; Masters, Colin L.; Tanzi, Rudolph E.; Inestrosa, Nibaldo C.; Bush, Ashley I.

doi:10.1074/jbc.m206428200

Cited by 556 publications

(390 citation statements)

References 48 publications

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“…Finally, a significant dysfunction in calcium homeostasis with A␤ is in good agreement with several studies that related AD to ion alterations, with calcium being central to these mechanisms (43). However, the contribution of other ions such as copper, iron, or zinc to the mechanism behind A␤ synaptotoxicity cannot be ruled out (44). In fact, histidine 13 and 14 of the A␤ sequence, corresponding to key amino acids for the metalbinding site of this peptide, are also determinants for the A␤ pore permeability (45).…”

Section: Effects Of Low A␤ Concentrations On Synaptic Transmission-supporting

confidence: 71%

β-Amyloid Causes Depletion of Synaptic Vesicles Leading to Neurotransmission Failure

Parodí

Sepúlveda

Roa

et al. 2010

Journal of Biological Chemistry

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164

120

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Alzheimer disease is a progressive neurodegenerative brain disorder that leads to major debilitating cognitive deficits. It is believed that the alterations capable of causing brain circuitry dysfunctions have a slow onset and that the full blown disease may take several years to develop. Therefore, it is important to understand the early, asymptomatic, and possible reversible states of the disease with the aim of proposing preventive and disease-modifying therapeutic strategies. It is largely unknown how amyloid ␤-peptide (A␤), a principal agent in Alzheimer disease, affects synapses in brain neurons. In this study, we found that similar to other pore-forming neurotoxins, A␤ induced a rapid increase in intracellular calcium and miniature currents, indicating an enhancement in vesicular transmitter release. Significantly, blockade of these effects by low extracellular calcium and a peptide known to act as an inhibitor of the A␤-induced pore prevented the delayed failure, indicating that A␤ blocks neurotransmission by causing vesicular depletion. This new mechanism for A␤ synaptic toxicity should provide an alternative pathway to search for small molecules that can antagonize these effects of A␤.

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Section: Effects Of Low A␤ Concentrations On Synaptic Transmission-supporting

confidence: 71%

β-Amyloid Causes Depletion of Synaptic Vesicles Leading to Neurotransmission Failure

Parodí

Sepúlveda

Roa

et al. 2010

Journal of Biological Chemistry

Self Cite

164

120

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“…On the other hand, three molar equivalents of Cu 2+ (Aβ 1-42 -3Cu 2+ ) was equivalent to free Cu 2+ suggesting an overload of inhibition. In this regard, Opazo et al reported that Aβ 1-42 purified from Alzheimer's disease plaque binds two molar equivalents of Cu 2+ , and it acts as pro-oxidant to generate hydrogen peroxide in the presence of reductant (27). The Aβ 1-42 -2Cu 2+ and Aβ 1-42 -3Cu 2+ generated hydrogen peroxide in the presence of ascorbate much the same as ascorbate-oxidase activity and HNE formation (unpublished result).…”

Section: Discussionmentioning

confidence: 86%

“…2+ . It has been reported that Aβ has an ability to bind up to 3.5 molar equivalents of Cu 2+ (37), and Aβ 1-42 binding two molar equivalents of Cu 2+ (Aβ 1-42 -2Cu 2+ ) generates hydrogen peroxide in the presence of reductant (27). Aβ 1-42 with equimolar Cu 2+ decreased HNE formation by 91% as compared to free Cu 2+ (Fig.…”

Section: Decomposition Of Plpc-ooh and Formation Of Hne By Cu 2+mentioning

confidence: 87%

“…Lipid hydroperoxides are generally known to be degraded by transition metal ions and is known that Aβ shows a strong affinity for transition metal ions, especially Cu 2+ such that Aβ is assumed to bind with Cu 2+ physiologically (19)(20)(21)(22)(23). The Aβ-Cu 2+ complex is reported to act as a pro-oxidant (24)(25)(26)(27), an especially deleterious aspect since Aβ is rich in hydrophobic amino acids in the carboxyl-terminal region and is present in phospholipids with lipoproteins of both cerebrospinal fluid and plasma (28,29).…”

Section: Introductionmentioning

confidence: 99%

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Lipid peroxidation and 4-hydroxy-2-nonenal formation by copper ion bound to amyloid-β peptide

Hayashi

Takahashi‐Shishido

Nakayama

et al. 2007

Free Radical Biology and Medicine

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Abstract-The lipid peroxidation product 4-hydroxy-2-nonenal (HNE) is proposed to be a toxic factor in the pathogenesis of Alzheimer's disease. The primary products of lipid peroxidation are phospholipid hydroperoxides and degraded reactive aldehydes, such as HNE, as secondary peroxidation products. In this study, we investigated the role of amyloid-β peptide (Aβ) in the formation of phospholipid hydroperoxides and HNE by copper ion bound to Aβ. The Aβ 1-42 -Cu 2+ (1:1 molar ratio) complex showed an activity to form phospholipid hydroperoxides from phospholipid, 1-palmitoyl-2-linoleoyl phosphatidylcholine (PLPC), through Cu 2+ reduction in the presence of ascorbic acid. The phospholipid hydroperoxides were considered to be racemic mixture of 9-hydroperoxide and 13-hydroperoxide of linoleoyl residue. When Cu 2+ was bound to two molar equivalents of Aβ 1-42 (2 Aβ 1-42 -Cu 2+ ), lipid peroxidation was inhibited.

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“…6,7 Several in vitro studies have related the formation of the deposits and the observed toxicity to the interaction of Aβ with these metal cations. [8][9][10][11][12][13][14] In this sense, copper has been the most intensively studied [15][16][17][18][19][20][21][22] because of its abundance in the cerebral medium and its high redox activity. In particular, several studies have focused in the determination of the copper coordination center at different pH values by means of continuous wave electron paramagnetic resonance (CW-EPR) and hyperfine sublevel correlation (HYSCORE) spectroscopy.…”

Section: Introductionmentioning

confidence: 99%

Modeling Cu2+-Aβ complexes from computational approaches

et al. 2015

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Amyloid plaques formation and oxidative stress are two key events in the pathology of the Alzheimer disease (AD), in which metal cations have been shown to play an important role. In particular, the interaction of the redox active Cu2+ metal cation with Aβ has been found to interfere in amyloid aggregation and to lead to reactive oxygen species (ROS). A detailed knowledge of the electronic and molecular structure of Cu2+-Aβ complexes is thus important to get a better understanding of the role of these complexes in the development and progression of the AD disease. The computational treatment of these systems requires a combination of several available computational methodologies, because two fundamental aspects have to be addressed: the metal coordination sphere and the conformation adopted by the peptide upon copper binding. In this paper we review the main computational strategies used to deal with the Cu2+-Aβ coordination and build plausible Cu2+-Aβ models that will afterwards allow determining physicochemical properties of interest, such as their redox potential.

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Metalloenzyme-like Activity of Alzheimer's Disease β-Amyloid

Cited by 556 publications

References 48 publications

β-Amyloid Causes Depletion of Synaptic Vesicles Leading to Neurotransmission Failure

β-Amyloid Causes Depletion of Synaptic Vesicles Leading to Neurotransmission Failure

Lipid peroxidation and 4-hydroxy-2-nonenal formation by copper ion bound to amyloid-β peptide

Modeling Cu2+-Aβ complexes from computational approaches

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