Investigations of the Molecular Mechanism of Metal-Induced Aβ (1−40) Amyloidogenesis

Lim, Kwang Hun; Kim, Yun Kyung; Chang, Young‐Tae

doi:10.1021/bi701112z

Cited by 68 publications

(79 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Uniquely, equimolar conditions exhibit decreased initial metal-induced A␤ aggregation and a slow constant disappearance rate of both A␤ and Cu(II). An explanation could be that several conformations of the soluble Cu-A␤ complex exist (42,58), and that the conformational equilibrium of this complex is affected by the metal:peptide ratio (16,23,39). EPR (62)(63)(64) and stopped-flow fluorescence experiments (27) with A␤ and Cu(II) confirm the co-existence of at least two different A␤-Cu conformations at neutral pH.…”

Section: Aβ Monomermentioning

confidence: 93%

“…In all events elucidating the underlying molecular mechanisms of the A␤-Cu, interactions are vital for understanding the role of Cu(II) in the pathology of AD, and hence in developing new therapeutic strategies for the treatment of AD (7,22). Despite extensive studies, however, these mechanisms remain largely unsettled and conflicting effects have been reported; in some studies Cu(II) appears to be involved in amyloid oligomerization (4,23,24), other studies report that Cu(II) does enhance aggregation but only along non-amyloidogenic pathways (17,25), or even that Cu(II) inhibits the aggregation of A␤ (26). We recently showed that Cu(II) could induce both oligomerization and non-oligomerization pathways of A␤ on the millisecond-second time scale (27).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Cu(II) Mediates Kinetically Distinct, Non-amyloidogenic Aggregation of Amyloid-β Peptides

Pedersen

Østergaard

Rozlosnik

et al. 2011

Journal of Biological Chemistry

118

160

View full text Add to dashboard Cite

Cu(II) ions are implicated in the pathogenesis of Alzheimer disease by influencing the aggregation of the amyloid-␤ (A␤)peptide. Elucidating the underlying Cu(II)-induced A␤ aggregation is paramount for understanding the role of Cu(II) in the pathology of Alzheimer disease. The aim of this study was to characterize the qualitative and quantitative influence of Cu(II) on the extracellular aggregation mechanism and aggregate morphology of A␤ 1-40 using spectroscopic, microelectrophoretic, mass spectrometric, and ultrastructural techniques. We found that the Cu(II):A␤ ratio in solution has a major influence on (i) the aggregation kinetics/mechanism of A␤, because three different kinetic scenarios were observed depending on the Cu(II):A␤ ratio, (ii) the metal:peptide stoichiometry in the aggregates, which increased to 1.4 at supra-equimolar Cu(II):A␤ ratio; and (iii) the morphology of the aggregates, which shifted from fibrillar to non-fibrillar at increasing Cu(II):A␤ ratios. We observed dynamic morphological changes of the aggregates, and that the formation of spherical aggregates appeared to be a common morphological end point independent on the Cu(II) concentration. Experiments with A␤ 1-42 were compatible with the conclusions for A␤ 1-40 even though the low solubility of A␤ 1-42 precluded examination under the same conditions as for the A␤ 1-40 . Experiments with A␤ 1-16 and A␤ 1-28 showed that other parts than the Cu(II)-binding His residues were important for Cu(II)-induced A␤ aggregation. Based on this study we propose three mechanistic models for the Cu(II)-induced aggregation of A␤ 1-40 depending on the Cu(II):A␤ ratio, and identify key reaction steps that may be feasible targets for preventing Cu(II)-associated aggregation or toxicity in Alzheimer disease.Extracellular cerebral plaques composed mainly of amyloid ␤-peptide (A␤) 1-40 and 1-42 fibrils are a histopathological hallmark of Alzheimer disease (AD) 3 (1, 2). These plaques contain elevated levels of metals, in particular zinc and copper (3). Also, it has been shown that these metal ions can promote the aggregation of A␤ in vitro (4, 5). This implies a key role of the metal ions in the A␤-mediated pathology of AD (6), although the subject is still under much debate (7,8), and a role of amyloid-independent pathways in AD neurodegeneration have recently been reviewed (9).Specifically regarding the role of metal ions in the amyloidmediated pathology of AD, it is believed that Zn(II) acts as a neuroprotector (10, 11), whereas Cu(II) is considered to mediate neurotoxicity (12)(13)(14). The latter effect is thought to occur through early stage soluble A␤ and A␤-Cu oligomeric intermediates (15-18) that may be involved in the formation of reactive oxygen species (6). It was discovered that Cu(II) may be released postsynaptically at glutamatergic synapses in hippocampus (19,20), the site for initial A␤ deposition in AD. This provides an explanation for how Cu(II) can interact with A␤. Seemingly in contrast to the support for the neurotoxic effects of Cu(II),...

show abstract

Section: Aβ Monomermentioning

confidence: 93%

mentioning

confidence: 99%

Cu(II) Mediates Kinetically Distinct, Non-amyloidogenic Aggregation of Amyloid-β Peptides

Pedersen

Østergaard

Rozlosnik

et al. 2011

Journal of Biological Chemistry

118

160

View full text Add to dashboard Cite

show abstract

“…Zinc has a crucial role in Ab aggregation, which is the most well-established contribution that zinc may have in AD pathogenesis. Aggregation of Ab peptides into protease-resistant deposits can be rapidly induced in the presence of zinc ions under physiological conditions in vitro (34,35). Zn binds to Ab in a monomeric and stoichiometric Zn-Ab complex, which is transiently stable prior to aggregation; the structure of the aggregates was described to be more amorphous, i.e., to contain less fibril (36).…”

Section: Zincmentioning

confidence: 99%

Metal ions, Alzheimer's disease and chelation therapy

Budimir¹

2011

Acta Pharmaceutica

176

113

View full text Add to dashboard Cite

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease, clinically characterized by memory and cognitive dysfunctions. It is primarily a disease of old age (1) and is the most prevalent cause of dementia in elderly people (2). AD affects about 35 million people worldwide today (3) and it is estimated to nearly double every 20 years, to reach 66 million in 2030, and 115 million in 2050 (3). There is no known cause and no cure for AD and these numbers makes finding a cure or rational treatment for AD an urgent priority. Despite significant advances in understanding the neuropathological and neurochemical events taking place in AD, the etiopathogenesis of progressive and mental cognitive dysfunction associated with aging remains largely unclear.Pathologically, AD is characterized by neuronal degeneration. The brains of AD patients are mainly characterized by extracellular proteic (or neuritic) deposits (amyloid or senile plaques) surrounded by dystrophic neuritic and intracellular neurofibrillary tangles (NFT) (4). The plaques and tangles are present mainly in brain regions involved in learning and memory and emotional behavior such as the entorhinal cortex, hippocam- In the last few years, various studies have been providing evidence that metal ions are critically involved in the pathogenesis of major neurological diseases (Alzheimer, Parkinson). Metal ion chelators have been suggested as potential therapies for diseases involving metal ion imbalance. Neurodegeneration is an excellent target for exploiting the metal chelator approach to therapeutics. In contrast to the direct chelation approach in metal ion overload disorders, in neurodegeneration the goal seems to be a better and subtle modulation of metal ion homeostasis, aimed at restoring ionic balance. Thus, moderate chelators able to coordinate deleterious metals without disturbing metal homeostasis are needed. To date, several chelating agents have been investigated for their potential to treat neurodegeneration, and a series of 8-hydroxyquinoline analogues showed the greatest potential for the treatment of neurodegenerative diseases.

show abstract

“…Studies suggested that H6, H13, and H14 at the N-terminal domain of Aβ coordinate with Zn 2þ (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Solution NMR of Zn 2þ -Aβ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] showed that Zn 2þ is bound to these three histidines and E11 (18). A recent NMR study of Zn 2þ -Aβ proposed that Zn 2þ binds to H6, E11, H14, and D1 of rat Aβ 1-28 and to H6, E11, H13, H14, and D1 of human Aβ 1-28 (22).…”

mentioning

confidence: 99%

Zinc ions promote Alzheimer Aβ aggregation via population shift of polymorphic states

Miller

Ma²,

Nussinov³

2010

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

283

288

View full text Add to dashboard Cite

Although a key factor in Alzheimer's disease etiology is enrichment of Zn 2þ in aggregates, and there are data suggesting that zinc promotes aggregation, how Zn 2þ -Aβ coordination promotes aggregation is elusive. Here we probe the structures and mechanisms through which Zn 2þ can affect amyloidosis. By covalently linking fragments (that have experiment-based coordinates) we observed that, in oligomeric Zn 2þ -Aβ 42 , Zn 2þ can simultaneously coordinate intra-and intermolecularly, bridging two peptides. Zinc coordination significantly decreases the solvation energy for large Zn 2þ -Aβ 42 oligomers and thus enhances their aggregation tendency. Zn 2þ binding does not change the β-sheet association around the C-terminal hydrophobic region; however, it shifts the relative population of the preexisting amyloid polymorphic ensembles. As a result, although a parallel β-sheet arrangement is still preferred, antiparallel and other less structured assemblies are stabilized, also becoming major species. Overall, Zn 2þ coordination promotes Aβ 42 aggregation leading to less uniform structures. Our replica exchange molecular dynamics simulations further reproduced an experimental observation that the increasing Zn 2þ concentration could slow down the aggregation rate, even though the aggregation rates are still much higher than in Zn 2þ -free solution.conformational selection | energy landscape | metal ions | modeling amyloid assemblies | seed polymorphism A lzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia in millions of people worldwide (1). This disease accounts for the majority of clinical senile dementia associated with the formation of senile plaques (2, 3). The primary constituent of the plaques is the aggregated Aβ 40 ∕Aβ 42 peptides in the brain; therefore, factors that influence the aggregation are of high interest.In vivo studies reported that Zn 2þ , Cu þ2 , and Fe þ3 are markedly enriched in Aβ plaques (4, 5), suggesting that these ions may act as seeding factors. Oligomerization of the Aβ peptides can be rapidly induced in the presence of Zn 2þ ions under physiological conditions (4, 6, 7). Noy et al. (8) have followed Zn 2þ ionenhanced Aβ aggregation. Studies suggested that H6, H13, and H14 at the N-terminal domain of Aβ coordinate with Zn 2þ (9-26). Solution NMR of Zn 2þ -Aβ 1-16 showed that Zn 2þ is bound to these three histidines and E11 (18). A recent NMR study of Zn 2þ -Aβ 1-28 proposed that Zn 2þ binds to H6, E11, H14, and D1 of rat Aβ 1-28 and to H6, E11, H13, H14, and D1 of human Aβ 1-28 (22). In addition, X-ray absorption spectroscopy revealed that Zn 2þ coordinates with four histidines, H13 and H14 of two adjacent monomers (23). Experimental structural data for Aβ 40 ∕Aβ 42 oligomers complexed with Zn 2þ are unavailable.Although it is believed that reducing zinc-induced Aβ aggregation can decrease toxicity (27), it was also postulated that zinc can lower Aβ toxicity by selectively precipitating aggregation intermediates (28). Key questions on the...

show abstract

Investigations of the Molecular Mechanism of Metal-Induced Aβ (1−40) Amyloidogenesis

Cited by 68 publications

References 80 publications

Cu(II) Mediates Kinetically Distinct, Non-amyloidogenic Aggregation of Amyloid-β Peptides

Cu(II) Mediates Kinetically Distinct, Non-amyloidogenic Aggregation of Amyloid-β Peptides

Metal ions, Alzheimer's disease and chelation therapy

Zinc ions promote Alzheimer Aβ aggregation via population shift of polymorphic states

Contact Info

Product

Resources

About