Identification and characterization of key kinetic intermediates in amyloid β-protein fibrillogenesis11Edited by F. Cohen

Kirkitadze, Marina; Condron, Margaret M.; Teplow, David B.

doi:10.1006/jmbi.2001.4970

Cited by 673 publications

(842 citation statements)

References 105 publications

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“…Similar interactions of Aβ, for example, with α-synuclein (Yoshimoto et al ., 1995) in the case of DLB, may lead to α-helical Aβ peptide species in vivo . The transient formation of an α-helix has been reported to play a major role in the assembly of toxic oligomers (Klimov and Thirumalai, 2003) and β-sheet formation, suggesting it to be an on-pathway to aggregation of Aβ (Kirkitadze et al ., 2001). …”

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

186

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%

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

Bibl¹,

Mollenhauer²,

Esselmann³

et al. 2006

Brain

186

146

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“…The observed intermediary helix structure in our simulations, stabilized by the V24-K28 hydrophobic interaction, is in accord with the experimental α-helix structures observed during the fibrilization process of the Aβ 1-40 -protein. 39 The V24-K28 hydrophobic interaction is destabilized by removing of the solvation water in the putative protofibril structures of Aβ 1-40 30,31 and Aβ 1-42 32 proteins.…”

Section: Charge States and Shifts In Population In Aggregation-prone mentioning

confidence: 99%

Structures and Free-Energy Landscapes of the Wild Type and Mutants of the Aβ21–30 Peptide Are Determined by an Interplay between Intrapeptide Electrostatic and Hydrophobic Interactions

Tarus

Straub

Thirumalai

2008

Journal of Molecular Biology

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The initial events in protein aggregation involve fluctuations that populate monomer conformations which lead to oligomerization and fibril assembly. The highly populated structures, driven by a balance between hydrophobic and electrostatic interactions in the protease-resistant wild type Aβ 21-30 -peptide and mutants E22Q (Dutch), D23N (Iowa), and K28N, are analyzed using molecular dynamics simulations. Intra-peptide electrostatic interactions were connected to calculated pK a values that compare well with the experimental estimates. The pK a values of the titratable residues show that E22 and D23 side-chains form salt-bridges only infrequently with the K28 side-chain. Contacts between E22-K28 are more probable in "dried" salt-bridges whereas D23-K28 contacts are more probable in solvated salt-bridges. The strength of the intra-peptide hydrophobic interactions increase as D23N

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“…An on-pathway mechanism which begins from random coils to ordered b-sheet binding fibrils via a variety of intermediates, including transiently a-helix-folded monomers, a-helical oligomers, b-sheet binding oligomers, has been suggested for self-assembly of amyloid peptides [18,[21][22][23][24][25][26][27][28]. The design of the inhibitors specifically targeting one of these types of intermediates could be very significant but also rather difficult.…”

Section: Introductionmentioning

confidence: 99%

“…In the current study, we used an all-D-amino-acid substituent of NFGAIL (hIAPP [22][23][24][25][26][27] as inhibitor to probe its potency and mechanism in preventing fibril formation of hIAPP both in bulk solution and at membrane surface by monitoring the dynamic processes, size distribution, structure details and morphologies of hIAPP aggregation in the absence and presence of the inhibitor.…”

Section: Introductionmentioning

confidence: 99%

A hIAPP‐derived all‐d‐amino‐acid inhibits hIAPP fibrillation efficiently at membrane surface by targeting α‐helical oligomeric intermediates

Wang

Lei

et al. 2014

FEBS Letters

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Edited by Sandro Sonnino ) is demonstrated to inhibit hIAPP fibril formation efficiently both at the phospholipid membrane and in bulk solution. The inhibitor terminates hIAPP aggregation to the a-helical oligomeric intermediates at the membrane surface, whereas it stops the aggregation at the stage of b-sheet oligomeric intermediates in bulk solution. This is the first evidence that the inhibition mechanism of the inhibitor at membrane surface is significantly different from that in bulk solution. Structured summary of protein interactions:hIAPP and hIAPP bind by transmission electron microscopy (View interaction) hIAPP and hIAPP bind by atomic force microscopy (View interaction) hIAPP and hIAPP bind by fluorescence technology (View interaction) hIAPP and hIAPP bind by dynamic light scattering (View interaction)

show abstract

Identification and characterization of key kinetic intermediates in amyloid β-protein fibrillogenesis11Edited by F. Cohen

Cited by 673 publications

References 105 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

Structures and Free-Energy Landscapes of the Wild Type and Mutants of the Aβ21–30 Peptide Are Determined by an Interplay between Intrapeptide Electrostatic and Hydrophobic Interactions

A hIAPP‐derived all‐d‐amino‐acid inhibits hIAPP fibrillation efficiently at membrane surface by targeting α‐helical oligomeric intermediates

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