Structural Characterization of a Soluble Amyloid β-Peptide Oligomer

Yu, Liping; Edalji, Rohinton; Harlan, John E.; Holzman, Thomas F.; Lopez, Ana Pereda; Labkovsky, Boris; Hillen, Heinz; Barghorn, Stefan; Ebert, Ulrich; Richardson, Paul L.; Miesbauer, Laura R.; Solomon, Larry R.; Bartley, Diane; Walter, Karl A.; Johnson, Robert W.; Hajduk, Philip J.; Olejniczak, Edward T.

doi:10.1021/bi802046n

Cited by 334 publications

(447 citation statements)

References 39 publications

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“…Our observations suggest that self-assembling of Ab(1-40) from oligomers to fibrils involves the central (aa [17][18][19][20][21][22][23][24] and C-terminal parts (aa 30-40) of the peptide (Fig. 3).…”

Section: Discussionmentioning

confidence: 72%

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Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Sarroukh

Cerf

Derclaye

et al. 2010

Cell. Mol. Life Sci.

137

119

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Alzheimer's disease (AD) is a neurodegenerative disorder occurring in the elderly. It is widely accepted that the amyloid beta peptide (Ab) aggregation and especially the oligomeric states rather than fibrils are involved in AD onset. We used infrared spectroscopy to provide structural information on the entire aggregation pathway of Ab(1-40), starting from monomeric Ab to the end of the process, fibrils. Our structural study suggests that conversion of oligomers into fibrils results from a transition from antiparallel to parallel b-sheet. These structural changes are described in terms of H-bonding rupture/formation, b-strands reorientation and b-sheet elongation. As antiparallel b-sheet structure is also observed for other amyloidogenic proteins forming oligomers, reorganization of the b-sheet implicating a reorientation of b-strands could be a generic mechanism determining the kinetics of protein misfolding. Elucidation of the process driving aggregation, including structural transitions, could be essential in a search for therapies inhibiting aggregation or disrupting aggregates.

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Section: Discussionmentioning

confidence: 72%

“…Despite the general interest concerning oligomers toxicity compared to fibrils, few structural data are available [17,18] and so far, no consensus model has been proposed. Nevertheless, infrared spectroscopy on Ab(1-40) [19] and [20,21] oligomers shows an antiparallel b-sheet organization.…”

Section: Introductionmentioning

confidence: 99%

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Sarroukh

Cerf

Derclaye

et al. 2010

Cell. Mol. Life Sci.

137

119

View full text Add to dashboard Cite

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“…Aggregated Aβ isolated from the brains of AD patients contains neurotoxic dimeric and trimeric species that are either formed in SDS-containing solutions or are resistant to denaturation in SDS/ PAGE electrophoresis experiments. It has been suggested that such species may constitute building blocks of toxic Aβ aggregates (3,18). If this suggestion is true and if the aggregates formed by AβCC are structurally identical to wild-type aggregates, then one would expect AβCC to form SDS-stable dimers.…”

Section: Resultsmentioning

confidence: 99%

“…There is also experimental evidence for the hairpin in oligomers of the globulomer kind (18), as well as for antiparallel β-sheet secondary structure in Aβ oligomers formed in TBS buffer or in cell culture medium (19). We therefore set out to test if stabilizing Aβ in the hairpin conformation observed in the Affibody complex would promote the formation of oligomeric aggregates but not fibrils, and whether such stabilized oligomers would possess antigenic and neurotoxic characteristics similar to those of wild-type Aβ oligomers found in AD.…”

mentioning

confidence: 99%

Stabilization of neurotoxic Alzheimer amyloid-β oligomers by protein engineering

Sandberg

Luheshi²,

Söllvander³

et al. 2010

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

323

405

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Soluble oligomeric aggregates of the amyloid-β peptide (Aβ) have been implicated in the pathogenesis of Alzheimer's disease (AD). Although the conformation adopted by Aβ within these aggregates is not known, a β-hairpin conformation is known to be accessible to monomeric Aβ. Here we show that this β-hairpin is a building block of toxic Aβ oligomers by engineering a doublecysteine mutant (called AβCC) in which the β-hairpin is stabilized by an intramolecular disulfide bond. Aβ 40 CC and Aβ 42 CC both spontaneously form stable oligomeric species with distinct molecular weights and secondary-structure content, but both are unable to convert into amyloid fibrils. Biochemical and biophysical experiments and assays with conformation-specific antibodies used to detect Aβ aggregates in vivo indicate that the wild-type oligomer structure is preserved and stabilized in AβCC oligomers. Stable oligomers are expected to become highly toxic and, accordingly, we find that β-sheet-containing Aβ 42 CC oligomers or protofibrillar species formed by these oligomers are 50 times more potent inducers of neuronal apoptosis than amyloid fibrils or samples of monomeric wild-type Aβ 42 , in which toxic aggregates are only transiently formed. The possibility of obtaining completely stable and physiologically relevant neurotoxic Aβ oligomer preparations will facilitate studies of their structure and role in the pathogenesis of AD. For example, here we show how kinetic partitioning into different aggregation pathways can explain why Aβ 42 is more toxic than the shorter Aβ 40 , and why certain inherited mutations are linked to protofibril formation and early-onset AD.amyloid-β peptide | protein aggregation | protein structure | protofibril | β-hairpin conformation

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“…This particular type of association might be favored for M35C because this mutation stabilizes the C-terminal parallel β-sheet characteristic for Aβ-globulomers corresponding to 12À16 peptides/soluble aggregate. 19 To investigate the homogeneity of the Aβ oligomers under native conditions, we purified the secreted Aβ oligomers by size exclusion chromatography (SEC) and Western blotted the fractions. By performing this analysis, we demonstrated that APP(AβS8C) was processed to yield exclusively dimeric Aβ (Figure 3c), whereas the M35C was assembling to a greater variety of high molecular weight species similar to the results in SDS-PAGE/Western blotting (Figure 3a, c).…”

Section: ' Results and Discussionmentioning

confidence: 99%

Molecular Engineering of a Secreted, Highly Homogeneous, and Neurotoxic Aβ Dimer

Müller‐Schiffmann¹,

Andreyeva²,

Horn

et al. 2011

ACS Chem. Neurosci.

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A lzheimer's disease (AD) is the most prevalent neurodegenerative disorder with the amyloid-β-peptide (Aβ) playing a central role in its pathogenesis. 1 Aβ is generated as a 38À43 residue peptide from the amyloid precursor protein (APP) by the proteolytic activity of β-and γ-secretases. 2,3 Aβ assembles into oligomers of various sizes and Aβ plaques, a neuropathological hallmark of AD. 1 Unlike Aβ fibrils or plaques, only the presence of Aβ oligomers correlates with the cognitive status of AD. 4,5 Aβ oligomers cause synaptic pathology 1,6 in line with findings that loss of dendritic spines correlates to early morphological changes in AD patients. 7 Many different oligomeric Aβ species have been identified, 8À10 and neurotoxicity has been attributed to Aβ dimers, 6 Aβ dodecamers, 10,11 or others. A recent study from Shankar et al. 6 has provided solid evidence that natively secreted Aβ dimers purified from post-mortem brains of patients with clinical AD are the predominant species sufficient to cause synaptic pathology. To gain insight into structureÀfunction relationships of Aβ dimers, it is of paramount importance to generate or purify highly homogeneous, distinct species of Aβ oligomers. So far, detailed structural investigations of native Aβ oligomers have been hampered by their low abundance in available transgenic mouse models of AD or AD patient brains, and laborious purification procedures.Synthetic Aβ has been a convenient tool for studying Aβ protein biochemistry, since it can be generated to relatively high purity in large amounts and is therefore readily available for biophysical and structural studies of some aspects of Aβ. However, evidence has accumulated suggesting that synthetic Aβ oligomers are only insufficiently modeling naturally secreted Aβ oligomer functions, even if refolded and purified by laborious procedures. Several studies clearly indicate that the bioactivity of naturally secreted Aβ oligomers from transfected cells is similar to that of AD brain-derived Aβ oligomers, but more than hundred times stronger than that of synthetic Aβ oligomers, when long-term potentiation (LTP) effects are taken as readout. 12 The major difference between natively secreted and synthetic Aβ is that natively secreted Aβ is the result of a highly controlled and quality-checked, cofactor-assisted proteolytic process at low local concentrations, while bulk refolding of synthetic Aβ occurs without regulating cofactors at high local concentrations. Bulk refolding leads to conformational heterogenetiy of refolded Aβ oligomers correlating with different neurotoxicities. 13 Received: February 20, 2011 Accepted: March 11, 2011 ABSTRACT: Aβ oligomers play a key role in the pathophysiology of Alzheimer's disease. Research into structureÀfunction relationships of Aβ oligomers has been hampered by the lack of large amounts of homogeneous and stable material. Using computational chemistry, we designed conservative cysteine substitutions in Aβ aiming at accelerating and stabilizing assembly of Aβ dimers by an intermolecu...

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Structural Characterization of a Soluble Amyloid β-Peptide Oligomer

Cited by 334 publications

References 39 publications

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Stabilization of neurotoxic Alzheimer amyloid-β oligomers by protein engineering

Molecular Engineering of a Secreted, Highly Homogeneous, and Neurotoxic Aβ Dimer

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