Human and rodent amyloid-β peptides differentially bind heme: Relevance to the human susceptibility to Alzheimer’s disease

Atamna, Hani; Frey, William H.; Ko, Novie

doi:10.1016/j.abb.2009.05.003

Cited by 81 publications

(148 citation statements)

References 56 publications

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“…It is important to note that rodent Ab, which lacks this Arg 5 residue (Fig. 1A), shows no significant enhancement in peroxidase activity relative to free heme [12], similar to Ab 1À16 (Arg 5 Asn) peptides (Fig. 1C).…”

Section: Arginine Residue Was Responsible For the Peroxidase Activitymentioning

confidence: 92%

“…The amino acid sequence of rodent Ab is identical to that of human Ab except for three amino acids (Arg 5 Gly 5 , Tyr 10 Phe 10 , His 13 Arg 13 ) within the hydrophilic region (Fig. 1A) implies possible important roles of the three residues of human Ab in AD pathology [12]. Furthermore, these amino acids Arg, Tyr, and His are found to participate in heme-binding in heme-proteins and peroxidases [12][13][14][15], which drive us to propose that Ab-heme peroxidase is a key molecular link between these residues present in human Ab and the increased human susceptibility to AD.…”

Section: Introductionmentioning

confidence: 95%

“…1A) implies possible important roles of the three residues of human Ab in AD pathology [12]. Furthermore, these amino acids Arg, Tyr, and His are found to participate in heme-binding in heme-proteins and peroxidases [12][13][14][15], which drive us to propose that Ab-heme peroxidase is a key molecular link between these residues present in human Ab and the increased human susceptibility to AD. Recent results showed that Arg 5 residue was required for Ab-heme peroxidase activity and His 13 and His 14 residues were the heme-binding ligands [16,17].…”

Section: Introductionmentioning

confidence: 97%

“…Ab, tightly bound to heme and formed a peroxidase-like complex. Although both human Ab and rodent Ab could form aggregates equally, rodents lack AD-like neuropathology [12]. These findings suggest that formation of Ab-heme peroxidase contributes to human Ab's neurotoxicity and the increased human susceptibility to AD.…”

Section: Introductionmentioning

confidence: 98%

See 3 more Smart Citations

Key roles of Arg5, Tyr10 and His residues in Aβ–heme peroxidase: Relevance to Alzheimer’s disease

Tian

et al. 2014

Biochemical and Biophysical Research Communications

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Section: Arginine Residue Was Responsible For the Peroxidase Activitymentioning

confidence: 92%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Key roles of Arg5, Tyr10 and His residues in Aβ–heme peroxidase: Relevance to Alzheimer’s disease

Tian

et al. 2014

Biochemical and Biophysical Research Communications

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“…Hemin and hematin (respectively 6.27a,b) bind preferentially to human Ab peptides [230]. They contribute to the inhibition of Ab aggregation and to the dismantling of Ab fibrils in neurons in basal conditions [231].…”

Section: Interfering With (Neuro)toxic Tau Species In the Aggregationmentioning

confidence: 99%

Targeting Assembly and Disassembly of Protein Aggregates

Seneci

2015

Chemical Modulators of Protein Misfolding and Neurodegenerative Disease

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Heme Binding Induces Dimerization and Nitration of Truncated β‐Amyloid Peptide Aβ16 Under Oxidative Stress

et al. 2013

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Several observations suggest a link between (ferric) heme and Alzheimers disease (AD), for example, an increase in heme oxygenase 1, [1,2] a loss of complex IV, [3][4][5][6] and abnormal iron metabolism. These observations suggest that heme metabolism is altered in age-related disorders. As a possible explanation, hemin has been proposed to interact with b-amyloid peptides (Ab), [7] and it is now well established that Ab peptides bind ferric heme. [8] The adducts of hemin-Ab peptides also exhibit increased peroxidase activity with respect to free hemin, [9] but these complexes have not been characterized. Herein we provide thermodynamic and spectroscopic data showing that hemin b can coordinate two Ab16 molecules to form the low-spin, six-coordinated complex [hemin(Ab16) 2 ], and this is in equilibrium with the high-spin [hemin(Ab16)] species, the relative amounts of which strongly depend on peptide concentration and temperature. In the presence of H 2 O 2 , hemin-Ab16 complexes produce dimerization of the peptide through dityrosine cross-linking, and in addition the peptide undergoes endogenous nitration at Tyr10 when nitrite is also present in solution. This result is important because both cross-linking and nitration at Tyr10 critically enhance Ab aggregation and plaque formation, [10] thus showing that the binding of heme to Ab can indeed be a factor contributing to neuroinflammation and Ab aggregation. The endogenous peroxidative (H 2 O 2 ) and nitrative (H 2 O 2 /NO 2 À ) activities exhibited by the hemin-Ab16 peptide add to, and are likely more deleterious than, the oxidation [9] and nitration [11] of external substrates which have been previously reported.Upon adding Ab16 to a 50 mm aqueous phosphate buffer solution of hemin b at pH 7.4 and 300 K, the broad Soret band of the complex near l = 385 nm progressively changes to give a sharp, red-shifted band at l = 414 nm, with additional visible bands at l = 535 and 566 nm (Figure 1 C, and see the Supporting Information). The conversion from the high-spin to the low-spin hemin species is complete after addition of 20 equivalents of Ab16, and spectrophotometric data analysis (see the Supporting Information) confirms a 2:1 Ab16/hemin stoichiometry, thus indicating the formation of the [hemin-(Ab16) 2 ] complex. The Mçssbauer and 1 H NMR spectra are consistent with a low-spin (S = 1/2) iron(III) center coordinated by two axial imidazole ligands. However, below saturating amounts of Ab16, the Mçssbauer spectrum clearly indicates the presence of a minor high-spin species (Figure 2). Figure 1. UV/vis spectra recorded in 50 mm phosphate buffer solution at pH 7.4. A) Hemin b (1.2 10 À5 m). B) Hemin b in the presence of an excess (20 equiv) of Ab16 peptide at 319 K. C) The same as (B) but at 300 K, the spectral changes are fully reversible. The D symbol indicates an increase in temperature.Figure 2. Mçssbauer spectrum of hemin b (2 mm), in the presence of 6 equivalents of the Ab16 peptide, recorded at 78 K. Quadrupole doublet simulation reveals the presence of a major...

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Human and rodent amyloid-β peptides differentially bind heme: Relevance to the human susceptibility to Alzheimer’s disease

Cited by 81 publications

References 56 publications

Key roles of Arg5, Tyr10 and His residues in Aβ–heme peroxidase: Relevance to Alzheimer’s disease

Key roles of Arg5, Tyr10 and His residues in Aβ–heme peroxidase: Relevance to Alzheimer’s disease

Targeting Assembly and Disassembly of Protein Aggregates

Heme Binding Induces Dimerization and Nitration of Truncated β‐Amyloid Peptide Aβ16 Under Oxidative Stress

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