Autocatalytic amplification of Alzheimer-associated Aβ42 peptide aggregation in human cerebrospinal fluid

Frankel, Rebecca; Törnquist, Mattias; Meisl, Georg; Hansson, Oskar; Andréasson, Ulf; Zetterberg, Henrik; Blennow, Kaj; Frohm, Birgitta; Cedervall, Tommy; Knowles, Tuomas P. J.; Leiding, Thom; Linse, Sara

doi:10.1038/s42003-019-0612-2

Cited by 49 publications

(42 citation statements)

References 55 publications

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“…The deterministic nature of the model, c.f. ( 3 ), has at least three distinct advantages over complex, stochastic models: first, the reaction terms of ( 3 ) represent simplified [ 49 , 50 ], but physical, protein aggregation kinetics with a basis in experimental measurement [ 50 , 52 , 53 , 54 , 56 ]; second, the connectome-discretized Eqs ( 8 )–( 11 ), can also be readily implemented using off-the-shelf mathematical software (e.g. Mathematica or Matlab, etc).…”

Section: Discussionmentioning

confidence: 99%

“…The heterodimer model views these three processes as a single step and expresses this step as an overall mean rate of reaction; such rates can be determined experimentally. Indeed, measuring the mean rates of protein self-aggregation mechanisms, providing best-fit mean aggregation dynamics to deterministic models such as the heterodimer model, is a thriving field of contemporary research [ 50 , 52 , 53 , 54 , 55 , 56 ] and our choice of a deterministic model is inspired by such work. Fig 20 demonstrates the primary molecular mechanism of the heterodimer model; the healthy (blue) protein is approached by the toxic (red) protein and undergoes three separate transitions (small arrows) which are treated as a single transition (long arrow) taking a healthy protein to a misfolded, toxic state.…”

Section: Methodsmentioning

confidence: 99%

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Protein-protein interactions in neurodegenerative diseases: A conspiracy theory

et al. 2020

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Neurodegenerative diseases such as Alzheimer’s or Parkinson’s are associated with the prion-like propagation and aggregation of toxic proteins. A long standing hypothesis that amyloid-beta drives Alzheimer’s disease has proven the subject of contemporary controversy; leading to new research in both the role of tau protein and its interaction with amyloid-beta. Conversely, recent work in mathematical modeling has demonstrated the relevance of nonlinear reaction-diffusion type equations to capture essential features of the disease. Such approaches have been further simplified, to network-based models, and offer researchers a powerful set of computationally tractable tools with which to investigate neurodegenerative disease dynamics. Here, we propose a novel, coupled network-based model for a two-protein system that includes an enzymatic interaction term alongside a simple model of aggregate transneuronal damage. We apply this theoretical model to test the possible interactions between tau proteins and amyloid-beta and study the resulting coupled behavior between toxic protein clearance and proteopathic phenomenology. Our analysis reveals ways in which amyloid-beta and tau proteins may conspire with each other to enhance the nucleation and propagation of different diseases, thus shedding new light on the importance of protein clearance and protein interaction mechanisms in prion-like models of neurodegenerative disease.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Protein-protein interactions in neurodegenerative diseases: A conspiracy theory

et al. 2020

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“…This process implies the de novo assembly of monomers onto the surface of pre-assembled aggregates and represents, therefore, a particular type of heterogeneous nucleation. The aggregation of the Aβ42 peptide into amyloid fibrils under typical physiological conditions in vitro has been shown to be dominated by secondary nucleation processes, once primary nucleation has been triggered [116]. The consequence is a significant amplification of the number of aggregates during the reaction, with the generation of significant concentrations of toxic oligomers [32].…”

Section: Secondary Processesmentioning

confidence: 99%

Multiplicity of α-Synuclein Aggregated Species and Their Possible Roles in Disease

Gracia

Camino

Volpicelli‐Daley

et al. 2020

IJMS

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α-Synuclein amyloid aggregation is a defining molecular feature of Parkinson’s disease, Lewy body dementia, and multiple system atrophy, but can also be found in other neurodegenerative disorders such as Alzheimer’s disease. The process of α-synuclein aggregation can be initiated through alternative nucleation mechanisms and dominated by different secondary processes giving rise to multiple amyloid polymorphs and intermediate species. Some aggregated species have more inherent abilities to induce cellular stress and toxicity, while others seem to be more potent in propagating neurodegeneration. The preference for particular types of polymorphs depends on the solution conditions and the cellular microenvironment that the protein encounters, which is likely related to the distinct cellular locations of α-synuclein inclusions in different synucleinopathies, and the existence of disease-specific amyloid polymorphs. In this review, we discuss our current understanding on the nature and structure of the various types of α-synuclein aggregated species and their possible roles in pathology. Precisely defining these distinct α-synuclein species will contribute to understanding the molecular origins of these disorders, developing accurate diagnoses, and designing effective therapeutic interventions for these highly debilitating neurodegenerative diseases.

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“…The heterodimer model views these three processes as a single step and expresses this step as an overall mean rate of reaction; such rates can be determined experimentally. Indeed, measuring the mean rates of protein self-aggregation mechanisms, providing best-fit mean aggregation dynamics to deterministic models such as the heterodimer model, is a thriving field of contemporary research [50,52,53,54,55,56] and our choice of a deterministic model is inspired by such work. Figure 1 demonstrates the primary molecular mechanism of the heterodimer model; the healthy (blue) protein is approached by the toxic (red) protein and undergoes three separate transitions (small arrows) which are treated as a single transition (long arrow) taking a healthy protein to a misfolded, toxic state.…”

Section: Continuous Modelmentioning

confidence: 99%

“…The deterministic nature of the model, c.f. (1), has at least three distinct advantages over complex, stochastic models: first, the reaction terms of (1) represent simplified [49,50], but physical, protein aggregation kinetics with a basis in experimental measurement [50,52,53,54,56]; second, the connectome-discretized equations, (6)- (9), can also be readily implemented using off-the-shelf mathematical software (e.g. Mathematica or Matlab, etc).…”

Section: Advantages and Limitationsmentioning

confidence: 99%

Protein-protein interactions in neurodegenerative diseases: a conspiracy theory

Thompson

Kuhl

Goriely

2020

Preprint

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Neurodegenerative diseases such as Alzheimer's or Parkinson's are associated with the prionlike propagation and aggregation of toxic proteins. A long standing hypothesis that amyloid-beta drives Alzheimer's disease has proven the subject of contemporary controversy; leading to new research in both the role of tau protein and its interaction with amyloid-beta. Conversely, recent work in mathematical modelling has demonstrated the relevance of nonlinear reaction-diffusion type equations to capture essential features of the disease. Such approaches have been further simplified, to network-based models, and offer researchers a powerful set of computationally tractable tools with which to investigate neurodegenerative disease dynamics.Here, we propose a novel, coupled network-based model for a two-protein system that includes an enzymatic interaction term alongside a simple model of aggregate transneuronal damage. We apply this model to test the possible interactions between tau proteins and amyloidbeta and study the complex coupled behaviour between toxic protein clearance and proteopathic propagation. This analysis reveals that amyloid-beta and tau proteins conspire with each other to enhance the nucleation and propagation of different diseases, thus shedding new light on the importance of protein clearance and protein interaction mechanisms in prion-like models of neurodegenerative disease. dominated the search for cures and treatments [5,6]. According to this hypothesis, an imbalance between production and clearance of Aβ42 and other Aβ peptides is not only an early indicator of the disease but the causing factor for its initiation, progression, and pathogenesis [7]. However, the repeated failures of large clinical trials focussing on the reduction of Aβ plaques has led many researchers to question the amyloid hypothesis and argue for the possible importance of other mechanisms.The obvious alternative is τ P that are usually considered secondary agents in the disease despite the fact that (1) other τ P-related diseases (tauopathies), such as frontotemporal lobar degeneration, are mostly dominated by τ P spreading [8];(2) brain atrophy in AD is directly correlated with large concentrations of NFT [9, 10]; (3) τ P distribution determines disease staging [11]; (4) lowering τ P levels prevent neuronal loss [12]; (5) τ P reduces neural activity and is the main factor associated with cognitive decline [13]. These findings may explain the relative lack of clinical improvements after Aβ suppression and the debate between the relative importance of Aβ proteopathy and τ P tauopathy in AD [14]. Furthermore, the similarity in mechanism and progression between prion diseases [15] and classical neurodegenerative diseases led to the formulation of the ''prion-like hypothesis" [16,17,18,19,20,21] stating that all these protein-related degenerative diseases are characterized by the progressive spreading and autocatalytic amplification of abnormal proteinaceous assemblies through axonal pathways [22].Since so many cellular mechanis...

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Autocatalytic amplification of Alzheimer-associated Aβ42 peptide aggregation in human cerebrospinal fluid

Cited by 49 publications

References 55 publications

Protein-protein interactions in neurodegenerative diseases: A conspiracy theory

Protein-protein interactions in neurodegenerative diseases: A conspiracy theory

Multiplicity of α-Synuclein Aggregated Species and Their Possible Roles in Disease

Protein-protein interactions in neurodegenerative diseases: a conspiracy theory

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