Rabia Sarroukh - Academia.edu (original) (raw)

Papers by Rabia Sarroukh

Most Alzheimer's disease (AD) cases are late-onset and characterized by the aggregation and depos... more Most Alzheimer's disease (AD) cases are late-onset and characterized by the aggregation and deposition of the amyloid-beta (Aβ) peptide in extracellular plaques in the brain. However, a few rare and hereditary Aβ mutations, such as the Italian Glu22-to-Lys (E22K) mutation, guarantee the development of early-onset familial AD. This type of AD is associated with a younger age at disease onset, increased β-amyloid accumulation, and Aβ deposition in cerebral blood vessel walls, giving rise to cerebral amyloid angiopathy (CAA). It remains largely unknown how the Italian mutation results in the clinical phenotype that is characteristic of CAA. We therefore investigated how this single point mutation may affect the aggregation of Aβ1-42 in vitro and structurally characterized the resulting fibrils using a biophysical approach. This paper reports that wild-type and Italian-mutant Aβ both form fibrils characterized by the cross-β architecture, but with distinct β-sheet organizations, resulting in differences in thioflavin T fluorescence and solvent accessibility. E22K Aβ1-42 oligomers and fibrils both display an antiparallel β-sheet structure, in comparison with the parallel β-sheet structure of wild-type fibrils, characteristic of most amyloid fibrils described in the literature. Moreover, we demonstrate structural plasticity for Italian-mutant Aβ fibrils in a pH-dependent manner, in terms of their underlying β-sheet arrangement. These findings are of interest in the ongoing debate that (1) antiparallel β-sheet structure might represent a signature for toxicity, which could explain the higher toxicity reported for the Italian mutant, and that (2) fibril polymorphism might underlie differences in disease pathology and clinical manifestation.

Biophysical Journal, 2012

Biochimica et Biophysica Acta (BBA) - Biomembranes, 2013

Amyloid refers to insoluble protein aggregates that are responsible for amyloid diseases but are ... more Amyloid refers to insoluble protein aggregates that are responsible for amyloid diseases but are also implicated in important physiological functions (functional amyloids). The widespread presence of protein aggregates but also, in most of the cases, their deleterious effects explain worldwide efforts made to understand their formation, structure and biological functions. We emphasized the role of FTIR and especially ATR-FTIR techniques in amyloid protein and/or peptide studies. The multiple advantages provided by ATR-FTIR allow an almost continuous structural view of protein/peptide conversion during the aggregation process. Moreover, it is now well-established that infrared can differentiate oligomers from fibrils simply on their spectral features. ATR-FTIR is certainly the fastest and easiest method to obtain this information. ATR-FTIR occupies a key position in the analysis and comprehension of the complex aggregation mechanism(s) at the oligomer and/or fibril level. These mechanism(s) seem to present strong similarities between different amyloid proteins and might therefore be extremely important to understand for both disease-associated and functional amyloid proteins. This article is part of a Special Issue entitled: FTIR in membrane proteins and peptide studies.

FEBS Letters, 2012

Aggregated forms of the amyloid-β peptide are hypothesized to act as the prime toxic agents in Al... more Aggregated forms of the amyloid-β peptide are hypothesized to act as the prime toxic agents in Alzheimer disease (AD). The in vivo amyloid-β peptide pool consists of both C- and N-terminally truncated or mutated peptides, and the composition thereof significantly determines AD risk. Other variations, such as biotinylation, are introduced as molecular tools to aid the understanding of disease mechanisms. Since these modifications have the potential to alter key aggregation properties of the amyloid-β peptide, we present a comparative study of the aggregation of a substantial set of the most common in vivo identified and in vitro produced amyloid-β peptides.

Alzheimer's & Dementia, 2010

age matched controls) and individuals with TBI (survival time 0-24 hours n ¼ 18, 1-28 days, n ¼ 6... more age matched controls) and individuals with TBI (survival time 0-24 hours n ¼ 18, 1-28 days, n ¼ 6, 1-32 years n ¼ 13) underwent 4G8 immunohistochemistry to detect amyloid-b and AT8 immunostaining to detect neurofibrillary tangles. Sections underwent semi-quantitative assessment of intraneuronal amyloid and tau immunostaining using a scoring system of 0-3 in the dentate gyrus, CA4, CA3, CA1 and subiculum. Results: Intraneuronal amyloid was detected in both control cases and in response to mild brain injury. There was a significant increase in intraneuronal amyloid in all fields of the hippocampus in the TBI cases compared with controls (p ¼ 0.0027 -0.0135). Intense immunostaining (grade 3) was present in 0-15% of control cases and 45-55% of TBI cases. Intraneuronal amyloid increased with increasing survival time following TBI and was most extensive in individuals who survived longest after injury (p ¼ 0.0035 -0.0087 compared to controls). There was no evidence of increased neurofibrillary tangles in the head injury as compared to controls. Conclusions: This study indicates that mild brain injury is sufficient to induce alterations in amyloid and highlights the need to understand more about the mechanisms by which injury can lead to AD. P1-235 AGGREGATION OF THE Ab(1-40) PEPTIDE: SECONDARY STRUCTURE CHANGE FROM OLIGOMERS TO FIBRILS

Biochimica et Biophysica Acta (BBA) - Biomembranes, 2013

Amyloid refers to insoluble protein aggregates that are responsible for amyloid diseases but are ... more Amyloid refers to insoluble protein aggregates that are responsible for amyloid diseases but are also implicated in important physiological functions (functional amyloids). The widespread presence of protein aggregates but also, in most of the cases, their deleterious effects explain worldwide efforts made to understand their formation, structure and biological functions. We emphasized the role of FTIR and especially ATR-FTIR techniques in amyloid protein and/or peptide studies. The multiple advantages provided by ATR-FTIR allow an almost continuous structural view of protein/peptide conversion during the aggregation process. Moreover, it is now well-established that infrared can differentiate oligomers from fibrils simply on their spectral features. ATR-FTIR is certainly the fastest and easiest method to obtain this information. ATR-FTIR occupies a key position in the analysis and comprehension of the complex aggregation mechanism(s) at the oligomer and/or fibril level. These mechanism(s) seem to present strong similarities between different amyloid proteins and might therefore be extremely important to understand for both disease-associated and functional amyloid proteins. This article is part of a Special Issue entitled: FTIR in membrane proteins and peptide studies.

Cellular and Molecular Life Sciences, 2011

Alzheimer's disease (AD) is a neurodegenerative disorder occurring in the elderly. It is widely a... more 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.

Biophysical Journal, 2012

Parkinson's disease is an age-related movement disorder characterized by the presence in the mid-... more Parkinson's disease is an age-related movement disorder characterized by the presence in the mid-brain of amyloid deposits of the 140-amino-acid protein AS (α-synuclein). AS fibrillation follows a nucleation polymerization pathway involving diverse transient prefibrillar species varying in size and morphology. Similar to other neurodegenerative diseases, cytotoxicity is currently attributed to these prefibrillar species rather than to the insoluble aggregates. Nevertheless, the underlying molecular mechanisms responsible for cytotoxicity remain elusive and structural studies may contribute to the understanding of both the amyloid aggregation mechanism and oligomer-induced toxicity. It is already recognized that soluble oligomeric AS species adopt β-sheet structures that differ from those characterizing the fibrillar structure. In the present study we used ATR (attenuated total reflection)-FTIR (Fourier-transform infrared) spectroscopy, a technique especially sensitive to β-sheet structure, to get a deeper insight into the β-sheet organization within oligomers and fibrils. Careful spectral analysis revealed that AS oligomers adopt an antiparallel β-sheet structure, whereas fibrils adopt a parallel arrangement. The results are discussed in terms of regions of the protein involved in the early βsheet interactions and the implications of such conformational arrangement for the pathogenicity associated with AS oligomers.

Biochemical Journal, 2012

Parkinson's disease is an age-related movement disorder characterized by the presence in the mid-... more Parkinson's disease is an age-related movement disorder characterized by the presence in the mid-brain of amyloid deposits of the 140-amino-acid protein AS (α-synuclein). AS fibrillation follows a nucleation polymerization pathway involving diverse transient prefibrillar species varying in size and morphology. Similar to other neurodegenerative diseases, cytotoxicity is currently attributed to these prefibrillar species rather than to the insoluble aggregates. Nevertheless, the underlying molecular mechanisms responsible for cytotoxicity remain elusive and structural studies may contribute to the understanding of both the amyloid aggregation mechanism and oligomer-induced toxicity. It is already recognized that soluble oligomeric AS species adopt β-sheet structures that differ from those characterizing the fibrillar structure. In the present study we used ATR (attenuated total reflection)-FTIR (Fourier-transform infrared) spectroscopy, a technique especially sensitive to β-sheet structure, to get a deeper insight into the β-sheet organization within oligomers and fibrils. Careful spectral analysis revealed that AS oligomers adopt an antiparallel β-sheet structure, whereas fibrils adopt a parallel arrangement. The results are discussed in terms of regions of the protein involved in the early βsheet interactions and the implications of such conformational arrangement for the pathogenicity associated with AS oligomers.

FEBS Letters, 2012

Aggregated forms of the amyloid-β peptide are hypothesized to act as the prime toxic agents in Al... more Aggregated forms of the amyloid-β peptide are hypothesized to act as the prime toxic agents in Alzheimer disease (AD). The in vivo amyloid-β peptide pool consists of both C- and N-terminally truncated or mutated peptides, and the composition thereof significantly determines AD risk. Other variations, such as biotinylation, are introduced as molecular tools to aid the understanding of disease mechanisms. Since these modifications have the potential to alter key aggregation properties of the amyloid-β peptide, we present a comparative study of the aggregation of a substantial set of the most common in vivo identified and in vitro produced amyloid-β peptides.

Food & Function, 2013

A proline-rich peptide product prepared from bovine whey protein that was enriched in several hyd... more A proline-rich peptide product prepared from bovine whey protein that was enriched in several hydrophobic amino acids including proline (whey proline-rich peptide, wPRP) was shown to modulate the folding pathway of human amyloid beta peptide 1-42 (Ab42) into oligomers. Concentrationdependent changes in ThT-binding to Ab42 by wPRP indicated suppression of oligomerisation, that was supported by Transmission Electron Microscopy. Suppression of b-sheet and specifically, antiparallel b-sheet structures by wPRP was demonstrated by ATR-FTIR spectroscopy, where evidence for capacity of wPRP to dissociate pre-existing b-sheet structures in Ab42 was also apparent. Suppression of anti-parallel b-sheets of oligomeric Ab42 was associated with rescue of yeast and SH-SY5Y neuronal cells providing important evidence for the association between anti-parallel b-sheet structure and oligomer toxicity. It was proposed that the interaction of wPRP with Ab42 interfered with the antiparallel folding pathway of oligomeric Ab42 and ultimately produced 'off-pathway' structures of lowered total b-sheet content, with attenuated cellular toxicity.

Parkinson's disease is an age-related movement disorder characterized by the presence in the mid-... more Parkinson's disease is an age-related movement disorder characterized by the presence in the mid-brain of amyloid deposits of the 140-amino-acid protein AS (α-synuclein). AS fibrillation follows a nucleation polymerization pathway involving diverse transient prefibrillar species varying in size and morphology. Similar to other neurodegenerative diseases, cytotoxicity is currently attributed to these prefibrillar species rather than to the insoluble aggregates. Nevertheless, the underlying molecular mechanisms responsible for cytotoxicity remain elusive and structural studies may contribute to the understanding of both the amyloid aggregation mechanism and oligomer-induced toxicity. It is already recognized that soluble oligomeric AS species adopt β-sheet structures that differ from those characterizing the fibrillar structure. In the present study we used ATR (attenuated total reflection)-FTIR (Fourier-transform infrared) spectroscopy, a technique especially sensitive to β-sheet structure, to get a deeper insight into the β-sheet organization within oligomers and fibrils. Careful spectral analysis revealed that AS oligomers adopt an antiparallel β-sheet structure, whereas fibrils adopt a parallel arrangement. The results are discussed in terms of regions of the protein involved in the early βsheet interactions and the implications of such conformational arrangement for the pathogenicity associated with AS oligomers.

Biochemical Journal, 2009

AD (Alzheimer's disease) is linked to Aβ (amyloid β-peptide) misfolding. Studies demonstrate that... more AD (Alzheimer's disease) is linked to Aβ (amyloid β-peptide) misfolding. Studies demonstrate that the level of soluble Aβ oligomeric forms correlates better with the progression of the disease than the level of fibrillar forms. Conformation-dependent antibodies have been developed to detect either Aβ oligomers or fibrils, suggesting that structural differences between these forms of Aβ exist. Using conditions which yield well-defined Aβ-(1-42) oligomers or fibrils, we studied the secondary structure of these species by ATR (attenuated total reflection)-FTIR (Fouriertransform infrared) spectroscopy. Whereas fibrillar Aβ was organized in a parallel β-sheet conformation, oligomeric Aβ displayed distinct spectral features, which were attributed to an antiparallel β-sheet structure. We also noted striking similarities between Aβ oligomers spectra and those of bacterial outer membrane porins. We discuss our results in terms of a possible organization of the antiparallel β-sheets in Aβ oligomers, which may be related to reported effects of these highly toxic species in the amyloid pathogenesis associated with AD.

Most Alzheimer's disease (AD) cases are late-onset and characterized by the aggregation and depos... more Most Alzheimer's disease (AD) cases are late-onset and characterized by the aggregation and deposition of the amyloid-beta (Aβ) peptide in extracellular plaques in the brain. However, a few rare and hereditary Aβ mutations, such as the Italian Glu22-to-Lys (E22K) mutation, guarantee the development of early-onset familial AD. This type of AD is associated with a younger age at disease onset, increased β-amyloid accumulation, and Aβ deposition in cerebral blood vessel walls, giving rise to cerebral amyloid angiopathy (CAA). It remains largely unknown how the Italian mutation results in the clinical phenotype that is characteristic of CAA. We therefore investigated how this single point mutation may affect the aggregation of Aβ1-42 in vitro and structurally characterized the resulting fibrils using a biophysical approach. This paper reports that wild-type and Italian-mutant Aβ both form fibrils characterized by the cross-β architecture, but with distinct β-sheet organizations, resulting in differences in thioflavin T fluorescence and solvent accessibility. E22K Aβ1-42 oligomers and fibrils both display an antiparallel β-sheet structure, in comparison with the parallel β-sheet structure of wild-type fibrils, characteristic of most amyloid fibrils described in the literature. Moreover, we demonstrate structural plasticity for Italian-mutant Aβ fibrils in a pH-dependent manner, in terms of their underlying β-sheet arrangement. These findings are of interest in the ongoing debate that (1) antiparallel β-sheet structure might represent a signature for toxicity, which could explain the higher toxicity reported for the Italian mutant, and that (2) fibril polymorphism might underlie differences in disease pathology and clinical manifestation.

Biophysical Journal, 2012

Biochimica et Biophysica Acta (BBA) - Biomembranes, 2013

Amyloid refers to insoluble protein aggregates that are responsible for amyloid diseases but are ... more Amyloid refers to insoluble protein aggregates that are responsible for amyloid diseases but are also implicated in important physiological functions (functional amyloids). The widespread presence of protein aggregates but also, in most of the cases, their deleterious effects explain worldwide efforts made to understand their formation, structure and biological functions. We emphasized the role of FTIR and especially ATR-FTIR techniques in amyloid protein and/or peptide studies. The multiple advantages provided by ATR-FTIR allow an almost continuous structural view of protein/peptide conversion during the aggregation process. Moreover, it is now well-established that infrared can differentiate oligomers from fibrils simply on their spectral features. ATR-FTIR is certainly the fastest and easiest method to obtain this information. ATR-FTIR occupies a key position in the analysis and comprehension of the complex aggregation mechanism(s) at the oligomer and/or fibril level. These mechanism(s) seem to present strong similarities between different amyloid proteins and might therefore be extremely important to understand for both disease-associated and functional amyloid proteins. This article is part of a Special Issue entitled: FTIR in membrane proteins and peptide studies.

FEBS Letters, 2012

Aggregated forms of the amyloid-β peptide are hypothesized to act as the prime toxic agents in Al... more Aggregated forms of the amyloid-β peptide are hypothesized to act as the prime toxic agents in Alzheimer disease (AD). The in vivo amyloid-β peptide pool consists of both C- and N-terminally truncated or mutated peptides, and the composition thereof significantly determines AD risk. Other variations, such as biotinylation, are introduced as molecular tools to aid the understanding of disease mechanisms. Since these modifications have the potential to alter key aggregation properties of the amyloid-β peptide, we present a comparative study of the aggregation of a substantial set of the most common in vivo identified and in vitro produced amyloid-β peptides.

Alzheimer's & Dementia, 2010

age matched controls) and individuals with TBI (survival time 0-24 hours n ¼ 18, 1-28 days, n ¼ 6... more age matched controls) and individuals with TBI (survival time 0-24 hours n ¼ 18, 1-28 days, n ¼ 6, 1-32 years n ¼ 13) underwent 4G8 immunohistochemistry to detect amyloid-b and AT8 immunostaining to detect neurofibrillary tangles. Sections underwent semi-quantitative assessment of intraneuronal amyloid and tau immunostaining using a scoring system of 0-3 in the dentate gyrus, CA4, CA3, CA1 and subiculum. Results: Intraneuronal amyloid was detected in both control cases and in response to mild brain injury. There was a significant increase in intraneuronal amyloid in all fields of the hippocampus in the TBI cases compared with controls (p ¼ 0.0027 -0.0135). Intense immunostaining (grade 3) was present in 0-15% of control cases and 45-55% of TBI cases. Intraneuronal amyloid increased with increasing survival time following TBI and was most extensive in individuals who survived longest after injury (p ¼ 0.0035 -0.0087 compared to controls). There was no evidence of increased neurofibrillary tangles in the head injury as compared to controls. Conclusions: This study indicates that mild brain injury is sufficient to induce alterations in amyloid and highlights the need to understand more about the mechanisms by which injury can lead to AD. P1-235 AGGREGATION OF THE Ab(1-40) PEPTIDE: SECONDARY STRUCTURE CHANGE FROM OLIGOMERS TO FIBRILS

Biochimica et Biophysica Acta (BBA) - Biomembranes, 2013

Amyloid refers to insoluble protein aggregates that are responsible for amyloid diseases but are ... more Amyloid refers to insoluble protein aggregates that are responsible for amyloid diseases but are also implicated in important physiological functions (functional amyloids). The widespread presence of protein aggregates but also, in most of the cases, their deleterious effects explain worldwide efforts made to understand their formation, structure and biological functions. We emphasized the role of FTIR and especially ATR-FTIR techniques in amyloid protein and/or peptide studies. The multiple advantages provided by ATR-FTIR allow an almost continuous structural view of protein/peptide conversion during the aggregation process. Moreover, it is now well-established that infrared can differentiate oligomers from fibrils simply on their spectral features. ATR-FTIR is certainly the fastest and easiest method to obtain this information. ATR-FTIR occupies a key position in the analysis and comprehension of the complex aggregation mechanism(s) at the oligomer and/or fibril level. These mechanism(s) seem to present strong similarities between different amyloid proteins and might therefore be extremely important to understand for both disease-associated and functional amyloid proteins. This article is part of a Special Issue entitled: FTIR in membrane proteins and peptide studies.

Cellular and Molecular Life Sciences, 2011

Alzheimer's disease (AD) is a neurodegenerative disorder occurring in the elderly. It is widely a... more 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.

Biophysical Journal, 2012

Parkinson's disease is an age-related movement disorder characterized by the presence in the mid-... more Parkinson's disease is an age-related movement disorder characterized by the presence in the mid-brain of amyloid deposits of the 140-amino-acid protein AS (α-synuclein). AS fibrillation follows a nucleation polymerization pathway involving diverse transient prefibrillar species varying in size and morphology. Similar to other neurodegenerative diseases, cytotoxicity is currently attributed to these prefibrillar species rather than to the insoluble aggregates. Nevertheless, the underlying molecular mechanisms responsible for cytotoxicity remain elusive and structural studies may contribute to the understanding of both the amyloid aggregation mechanism and oligomer-induced toxicity. It is already recognized that soluble oligomeric AS species adopt β-sheet structures that differ from those characterizing the fibrillar structure. In the present study we used ATR (attenuated total reflection)-FTIR (Fourier-transform infrared) spectroscopy, a technique especially sensitive to β-sheet structure, to get a deeper insight into the β-sheet organization within oligomers and fibrils. Careful spectral analysis revealed that AS oligomers adopt an antiparallel β-sheet structure, whereas fibrils adopt a parallel arrangement. The results are discussed in terms of regions of the protein involved in the early βsheet interactions and the implications of such conformational arrangement for the pathogenicity associated with AS oligomers.

Biochemical Journal, 2012

Parkinson's disease is an age-related movement disorder characterized by the presence in the mid-... more Parkinson's disease is an age-related movement disorder characterized by the presence in the mid-brain of amyloid deposits of the 140-amino-acid protein AS (α-synuclein). AS fibrillation follows a nucleation polymerization pathway involving diverse transient prefibrillar species varying in size and morphology. Similar to other neurodegenerative diseases, cytotoxicity is currently attributed to these prefibrillar species rather than to the insoluble aggregates. Nevertheless, the underlying molecular mechanisms responsible for cytotoxicity remain elusive and structural studies may contribute to the understanding of both the amyloid aggregation mechanism and oligomer-induced toxicity. It is already recognized that soluble oligomeric AS species adopt β-sheet structures that differ from those characterizing the fibrillar structure. In the present study we used ATR (attenuated total reflection)-FTIR (Fourier-transform infrared) spectroscopy, a technique especially sensitive to β-sheet structure, to get a deeper insight into the β-sheet organization within oligomers and fibrils. Careful spectral analysis revealed that AS oligomers adopt an antiparallel β-sheet structure, whereas fibrils adopt a parallel arrangement. The results are discussed in terms of regions of the protein involved in the early βsheet interactions and the implications of such conformational arrangement for the pathogenicity associated with AS oligomers.

FEBS Letters, 2012

Aggregated forms of the amyloid-β peptide are hypothesized to act as the prime toxic agents in Al... more Aggregated forms of the amyloid-β peptide are hypothesized to act as the prime toxic agents in Alzheimer disease (AD). The in vivo amyloid-β peptide pool consists of both C- and N-terminally truncated or mutated peptides, and the composition thereof significantly determines AD risk. Other variations, such as biotinylation, are introduced as molecular tools to aid the understanding of disease mechanisms. Since these modifications have the potential to alter key aggregation properties of the amyloid-β peptide, we present a comparative study of the aggregation of a substantial set of the most common in vivo identified and in vitro produced amyloid-β peptides.

Food & Function, 2013

A proline-rich peptide product prepared from bovine whey protein that was enriched in several hyd... more A proline-rich peptide product prepared from bovine whey protein that was enriched in several hydrophobic amino acids including proline (whey proline-rich peptide, wPRP) was shown to modulate the folding pathway of human amyloid beta peptide 1-42 (Ab42) into oligomers. Concentrationdependent changes in ThT-binding to Ab42 by wPRP indicated suppression of oligomerisation, that was supported by Transmission Electron Microscopy. Suppression of b-sheet and specifically, antiparallel b-sheet structures by wPRP was demonstrated by ATR-FTIR spectroscopy, where evidence for capacity of wPRP to dissociate pre-existing b-sheet structures in Ab42 was also apparent. Suppression of anti-parallel b-sheets of oligomeric Ab42 was associated with rescue of yeast and SH-SY5Y neuronal cells providing important evidence for the association between anti-parallel b-sheet structure and oligomer toxicity. It was proposed that the interaction of wPRP with Ab42 interfered with the antiparallel folding pathway of oligomeric Ab42 and ultimately produced 'off-pathway' structures of lowered total b-sheet content, with attenuated cellular toxicity.

Parkinson's disease is an age-related movement disorder characterized by the presence in the mid-... more Parkinson's disease is an age-related movement disorder characterized by the presence in the mid-brain of amyloid deposits of the 140-amino-acid protein AS (α-synuclein). AS fibrillation follows a nucleation polymerization pathway involving diverse transient prefibrillar species varying in size and morphology. Similar to other neurodegenerative diseases, cytotoxicity is currently attributed to these prefibrillar species rather than to the insoluble aggregates. Nevertheless, the underlying molecular mechanisms responsible for cytotoxicity remain elusive and structural studies may contribute to the understanding of both the amyloid aggregation mechanism and oligomer-induced toxicity. It is already recognized that soluble oligomeric AS species adopt β-sheet structures that differ from those characterizing the fibrillar structure. In the present study we used ATR (attenuated total reflection)-FTIR (Fourier-transform infrared) spectroscopy, a technique especially sensitive to β-sheet structure, to get a deeper insight into the β-sheet organization within oligomers and fibrils. Careful spectral analysis revealed that AS oligomers adopt an antiparallel β-sheet structure, whereas fibrils adopt a parallel arrangement. The results are discussed in terms of regions of the protein involved in the early βsheet interactions and the implications of such conformational arrangement for the pathogenicity associated with AS oligomers.

Biochemical Journal, 2009

AD (Alzheimer's disease) is linked to Aβ (amyloid β-peptide) misfolding. Studies demonstrate that... more AD (Alzheimer's disease) is linked to Aβ (amyloid β-peptide) misfolding. Studies demonstrate that the level of soluble Aβ oligomeric forms correlates better with the progression of the disease than the level of fibrillar forms. Conformation-dependent antibodies have been developed to detect either Aβ oligomers or fibrils, suggesting that structural differences between these forms of Aβ exist. Using conditions which yield well-defined Aβ-(1-42) oligomers or fibrils, we studied the secondary structure of these species by ATR (attenuated total reflection)-FTIR (Fouriertransform infrared) spectroscopy. Whereas fibrillar Aβ was organized in a parallel β-sheet conformation, oligomeric Aβ displayed distinct spectral features, which were attributed to an antiparallel β-sheet structure. We also noted striking similarities between Aβ oligomers spectra and those of bacterial outer membrane porins. We discuss our results in terms of a possible organization of the antiparallel β-sheets in Aβ oligomers, which may be related to reported effects of these highly toxic species in the amyloid pathogenesis associated with AD.