Interpreting the Aggregation Kinetics of Amyloid Peptides

Pellarin, Riccardo; Caflisch, Amedeo

doi:10.1016/j.jmb.2006.05.033

Cited by 241 publications

(294 citation statements)

References 50 publications

(48 reference statements)

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“…3). A similar heterogeneity has been described previously for in vitro fibrillation reactions as well (24,25), or molecular dynamics simulations (26). Such heterogeneity may arise from the stochastic nature of the nucleation reaction or from the formation of differently structured nuclei.…”

Section: Resultssupporting

confidence: 66%

Mechanism of amyloid plaque formation suggests an intracellular basis of Aβ pathogenicity

Friedrich

Tepper²,

Rönicke³

et al. 2010

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

268

211

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The formation of extracellular amyloid plaques is a common patho-biochemical event underlying several debilitating human conditions, including Alzheimer’s disease (AD). Considerable evidence implies that AD damage arises primarily from small oligomeric amyloid forms of Aβ peptide, but the precise mechanism of pathogenicity remains to be established. Using a cell culture system that reproducibly leads to the formation of Alzheimer’s Aβ amyloid plaques, we show here that the formation of a single amyloid plaque represents a template-dependent process that critically involves the presence of endocytosis- or phagocytosis-competent cells. Internalized Aβ peptide becomes sorted to multivesicular bodies where fibrils grow out, thus penetrating the vesicular membrane. Upon plaque formation, cells undergo cell death and intracellular amyloid structures become released into the extracellular space. These data imply a mechanism where the pathogenic activity of Aβ is attributed, at least in part, to intracellular aggregates.

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Section: Resultssupporting

confidence: 66%

Mechanism of amyloid plaque formation suggests an intracellular basis of Aβ pathogenicity

Friedrich

Tepper²,

Rönicke³

et al. 2010

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

268

211

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“…The driving forces and the mechanistic details of aggregation of blobsized peptides are similar to those of small molecules. This distinction is important in light of several experimental and computational studies, which focus on the aggregation of short peptides [34][35][36][37][38][39]. Here, we discuss the physical principles of polymer aggregation that are relevant to proteins with multiple segments of length g T .…”

Section: Distinction Between Aggregation Of Short Peptides and Full-lmentioning

confidence: 99%

A polymer physics perspective on driving forces and mechanisms for protein aggregation

Pappu

Wang

Vitalis

et al. 2008

Archives of Biochemistry and Biophysics

153

171

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Protein aggregation is a commonly occurring problem in biology. Cells have evolved stress-response mechanisms to cope with problems posed by protein aggregation. Yet, these quality control mechanisms are overwhelmed by chronic aggregation-related stress and the resultant consequences of aggregation become toxic to cells. As a result, a variety of systemic and neurodegenerative diseases are associated with various aspects of protein aggregation and rational approaches to either inhibit aggregation or manipulate the pathways to aggregation might lead to an alleviation of disease phenotypes. To develop such approaches, one needs a rigorous and quantitative understanding of protein aggregation. Much work has been done in this area. However, several unanswered questions linger, and these pertain primarily to the actual mechanism of aggregation as well as to the types of intermolecular associations and intramolecular fluctuations realized at low protein concentrations. It has been suggested that the concepts underlying protein aggregation are similar to those used to describe the aggregation of synthetic polymers. Following this suggestion, the relevant concepts of polymer aggregation are introduced. The focus is on explaining the driving forces for polymer aggregation and how these driving forces vary with chain length and solution conditions. It is widely accepted that protein aggregation is a nucleation-dependent process. This view is based mainly on the presence of long times for the accumulation of aggregates and the elimination of these lag times with "seeds". In this sense, protein aggregation is viewed as being analogous to the aggregation of colloidal particles. The theories for polymer aggregation reviewed in this work suggest an alternative mechanism for the origin of long lag times in protein aggregation. The proposed mechanism derives from the recognition that polymers have unique dynamics that distinguish them from other aggregation-prone systems such as colloidal particles.

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“…So far, the results we presented only involve the singlefibril case, which tries to mimic heterogeneous nucleation on a specific number of preset heterogeneous seeds ͑e.g., heterogeneous nucleation of A␤ [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] on A␤ [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] , 17 where homogeneous nucleation of A␤ [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] is unable to occur under the same conditions͒. When homogeneous nucleation occurs and an unspecific number of multiple...…”

Section: B Multiple Fibrilsmentioning

confidence: 99%

“…In a more recent off-lattice Langevin dynamics simulation, 41 self-assembly and chirality of the fibrillar aggregates from ␤ sheet forming short peptides were studied based on a coarse-grained united atom model. The influence 42 of intermediate states and reversibility of the polymerization process were addressed and it was shown 43 that the propensity of intermediates depends on the relative stability of ␤ prone conformational state. In contrast to these simulation models, our attempt here is to probe the later stages of nucleation of fibrils and their competitive growth.…”

Section: Introductionmentioning

confidence: 99%

Simulations of nucleation and elongation of amyloid fibrils

Zhang

Muthukumar

2009

The Journal of Chemical Physics

119

108

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We present a coarse-grained model for the growth kinetics of amyloid fibrils from solutions of peptides and address the fundamental mechanism of nucleation and elongation by using a lattice Monte Carlo procedure. We reproduce the three main characteristics of nucleation of amyloid fibrils: ͑1͒ existence of lag time, ͑2͒ occurrence of a critical concentration, and ͑3͒ seeding. We find the nucleation of amyloid fibrils to require a quasi-two-dimensional configuration, where a second layer of ␤ sheet must be formed adjunct to a first layer, which in turn leads to a highly cooperative nucleation barrier. The elongation stage is found to involve the Ostwald ripening ͑evaporation-condensation͒ mechanism, whereby bigger fibrils grow at the expense of smaller ones. This new mechanism reconciles the debate as to whether protofibrils are precursors or monomer reservoirs. We have systematically investigated the roles of time, peptide concentration, temperature, and seed size. In general, we find that there are two kinds of lag time arising from two different mechanisms. For higher temperatures or low enough concentrations close to the disassembly boundary, the fibrillization follows the nucleation mechanism. However, for low temperatures, where the nucleation time is sufficiently short, there still exists an apparent lag time due to slow Ostwald ripening mechanism. Consequently, the lag time is nonmonotonic with temperature, with the shortest lag time occurring at intermediate temperatures, which in turn depend on the peptide concentration. While the nucleation dominated regime can be controlled by seeding, the Ostwald ripening regime is insensitive to seeding. Simulation results from our coarse-grained model on the fibril size, lag time, elongation rate, and solubility are consistent with available experimental observations on many specific amyloid systems.

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Interpreting the Aggregation Kinetics of Amyloid Peptides

Cited by 241 publications

References 50 publications

Mechanism of amyloid plaque formation suggests an intracellular basis of Aβ pathogenicity

Mechanism of amyloid plaque formation suggests an intracellular basis of Aβ pathogenicity

A polymer physics perspective on driving forces and mechanisms for protein aggregation

Simulations of nucleation and elongation of amyloid fibrils

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