Kinetic Modulation of Amyloid-β (1–42) Aggregation and Toxicity by Structure-Based Rational Design

Im, Dongjoon; Heo, Chae Eun; Son, Myung Kook; Park, Chae Ri; Kim, Hugh I.; Choi, Jeong‐Mo

doi:10.1021/jacs.1c10173

Cited by 13 publications

(27 citation statements)

References 37 publications

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“…Since the self-assembly property of Aβ can be modulated by interrupting or enhancing the contact of the hydrophobic core domains, it would be possible to target the hydrophobic core regions in order to prevent or reduce the capacity of Aβ for self-assembling. Based on such findings, as well as in silico and in vitro analyses, we have previously shown that rationally designed point mutants of Aβ42 can suppress fibrillar aggregation . In particular, we identified two hydrophobic residues (Phe19 and Ile32) which are crucial for facilitating oligomerization of Aβ42 .…”

Section: Introductionmentioning

confidence: 74%

“…Recent studies have attempted to rationally design candidate drugs in order to improve existing therapeutic approaches or suppress the fibrillar amyloid aggregation process altogether − based on the accumulated knowledge of interlinked dynamics of IDPs, intermediate oligomers, and their pathogenesis to date. − For example, a pharmacophore in MAP tau for the binding of small molecules was shown to enhance the binding of potential therapeutic agents . In addition, an epitope-specific method for antibody design has been reported, which allows development of antibodies to the desired binding epitopes of amyloidogenic IDPs .…”

Section: Introductionmentioning

confidence: 99%

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Decoding the Roles of Amyloid-β (1–42)’s Key Oligomerization Domains toward Designing Epitope-Specific Aggregation Inhibitors

Kim

Yoon

et al. 2023

JACS Au

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Fibrillar amyloid aggregates are the pathological hallmarks of multiple neurodegenerative diseases. The amyloid-β (1–42) protein, in particular, is a major component of senile plaques in the brains of patients with Alzheimer’s disease and a primary target for disease treatment. Determining the essential domains of amyloid-β (1–42) that facilitate its oligomerization is critical for the development of aggregation inhibitors as potential therapeutic agents. In this study, we identified three key hydrophobic sites (17LVF19, 32IGL34, and 41IA42) on amyloid-β (1–42) and investigated their involvement in the self-assembly process of the protein. Based on these findings, we designed candidate inhibitor peptides of amyloid-β (1–42) aggregation. Using the designed peptides, we characterized the roles of the three hydrophobic regions during amyloid-β (1–42) fibrillar aggregation and monitored the consequent effects on its aggregation property and structural conversion. Furthermore, we used an amyloid-β (1–42) double point mutant (I41N/A42N) to examine the interactions between the two C-terminal end residues with the two hydrophobic regions and their roles in amyloid self-assembly. Our results indicate that interchain interactions in the central hydrophobic region (17LVF19) of amyloid-β (1–42) are important for fibrillar aggregation, and its interaction with other domains is associated with the accessibility of the central hydrophobic region for initiating the oligomerization process. Our study provides mechanistic insights into the self-assembly of amyloid-β (1–42) and highlights key structural domains that facilitate this process. Our results can be further applied toward improving the rational design of candidate amyloid-β (1–42) aggregation inhibitors.

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Section: Introductionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Decoding the Roles of Amyloid-β (1–42)’s Key Oligomerization Domains toward Designing Epitope-Specific Aggregation Inhibitors

Kim

Yoon

et al. 2023

JACS Au

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“…In T2D, hIAPP is secreted from islet β-cells, and its aggregation has been linked to β-cell destruction. − However, much therapeutic effort to target hIAPP aggregation failed to cure T2D. On the other hand, pramlintide, an FDA-approved drug for T2D, is a nonamyloidogenic hIAPP analogue. , Thus, we may speculate that nonamyloidogenic Aβ analogues may provide a new therapeutic approach toward AD treatments.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, pramlintide, an FDA-approved drug for T2D, is a nonamyloidogenic hIAPP analogue. 81,82 Thus, we may speculate that nonamyloidogenic Aβ analogues 83 may provide a new therapeutic approach toward AD treatments.…”

Section: ■ Conclusionmentioning

confidence: 99%

Potential Protective Function of Aβ₄₂ Monomer on Tauopathies

Gray

Norman

Oluwatoba

et al. 2023

J. Am. Soc. Mass Spectrom.

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While soluble forms of amyloid-β (Aβ) and Tau work together to drive healthy neurons into a disease state, how their interaction may control the prion-like propagation and neurotoxicity of Tau is not fully understood. The cross-linking via disulfide bond formation is crucial for Tau oligomers to obtain stable conformers and spread between cells. This work thus focuses on how Aβ42 regulates this critical process. By studying the interactions between Aβ42 and TauPHF43, a construct that mimics the Tau R3 isoform, has a similar length to Aβ42, and contains one cysteine (Cys-322), we discovered that fresh Aβ42 could protect Tau against the formation of disulfide cross-linked dimers. We showed that the monomeric and small Aβ oligomers (the “nonamyloidogenic Aβ”) efficiently disassembled tau dimers and heparin-induced Tau oligomers to recover Tau monomers. Interestingly, Aβ serves the role of an antioxidant to prevent disulfide bond formation, as supported by the experiments of Aβ with cystine. Furthermore, using cyclosporine A (CycA), a macrocyclic β-sheet disruptor, we demonstrated that targeting amyloidogenic Aβ with CycA does not affect the TauPHF43 disassembly driven by Aβ42. Separately, we assessed the initial toxicity of Aβ42 and TauPHF43 in acute brain slices and found that Aβ42 is more toxic than TauPHF43 or the two peptides combined. Our work highlights a potential protective role of Aβ42 monomers in AD that was previously overlooked while focusing on the mechanism behind Aβ42 aggregation leading to tau dysfunction.

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“…To initiate the aggregation process, it is necessary to create aggregation seeds first, which grow quickly after that. In experimental conditions, at the concentration of peptide in a µM range, the seeding of Aβ42 takes many hours [15,31]. By extrapolating to the interstitial concentration of beta-amyloid in vivo, which is in an nM range, the seeding would take several months [15].…”

Section: Formation Of Amyloid Depositsmentioning

confidence: 99%

Towards the integrative theory of Alzheimer’s disease: linking molecular mechanisms of neurotoxicity, beta-amyloid biomarkers, and the diagnosis

Molkov

Zaretskaia²,

Zaretsky³

2022

Preprint

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A major gap in amyloid-centric theories of Alzheimer′s disease (AD) is that even though amyloid fibrils per se are not toxic in vitro, the diagnosis of AD clearly correlates with the density of beta-amyloid (Aβ) deposits. Based on our proposed amyloid degradation toxicity hypothesis, we developed a mathematical model explaining this discrepancy. It suggests that cytotoxicity depends on the cellular uptake of soluble Aβ rather than on the presence of amyloid aggregates. The dynamics of soluble Aβ in the cerebrospinal fluid (CSF) and the density of Aβ deposits is described using a system of differential equations. In the model, cytotoxic damage is proportional to the cellular uptake of Aβ, while the probability of an AD diagnosis is defined by the Aβ cytotoxicity accumulated over the duration of the disease. After uptake, Aβ is concentrated intralysosomally, promoting the formation of fibrillation seeds inside cells. These seeds cannot be digested and are either accumulated intracellularly or exocytosed. Aβ starts aggregating on the extracellular seeds and, therefore, its concentration decreases in the interstitial fluid. The dependence of both Aβ toxicity and aggregation on the same process — cellular uptake of Aβ — explains the correlation between AD diagnosis and the density of amyloid aggregates in the brain. We tested the model using clinical data obtained from the Alzheimer′s Disease Neuroimaging Initiative (ADNI), which included records of beta-amyloid concentration in the cerebrospinal fluid (CSF-Aβ42) and the density of beta-amyloid deposits measured using positron emission tomography (PET). The model predicts the probability of AD diagnosis as a function of CSF-Aβ42 and PET and fits the experimental data at the 95% confidence level. Our study shows that existing clinical data allows for the inference of kinetic parameters describing beta-amyloid turnover and disease progression. Each combination of CSF-Aβ42 and PET values can be used to calculate the individual′s cellular uptake rate, the effective disease duration, and the accumulated toxicity. We show that natural limitations on these parameters explain the characteristic distribution of the clinical dataset for these two biomarkers in the population. The resulting mathematical model interprets the positive correlation between the density of Aβ deposits and the probability of an AD diagnosis without assuming any cytotoxicity of the aggregated beta-amyloid. Finally, to the best of our knowledge, this model is the first to mechanistically explain the negative correlation between the concentration of Aβ42 in the CSF and the probability of an AD diagnosis.

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Kinetic Modulation of Amyloid-β (1–42) Aggregation and Toxicity by Structure-Based Rational Design

Cited by 13 publications

References 37 publications

Decoding the Roles of Amyloid-β (1–42)’s Key Oligomerization Domains toward Designing Epitope-Specific Aggregation Inhibitors

Decoding the Roles of Amyloid-β (1–42)’s Key Oligomerization Domains toward Designing Epitope-Specific Aggregation Inhibitors

Potential Protective Function of Aβ₄₂ Monomer on Tauopathies

Towards the integrative theory of Alzheimer’s disease: linking molecular mechanisms of neurotoxicity, beta-amyloid biomarkers, and the diagnosis

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Kinetic Modulation of Amyloid-β (1–42) Aggregation and Toxicity by Structure-Based Rational Design

Cited by 13 publications

References 37 publications

Decoding the Roles of Amyloid-β (1–42)’s Key Oligomerization Domains toward Designing Epitope-Specific Aggregation Inhibitors

Decoding the Roles of Amyloid-β (1–42)’s Key Oligomerization Domains toward Designing Epitope-Specific Aggregation Inhibitors

Potential Protective Function of Aβ42 Monomer on Tauopathies

Towards the integrative theory of Alzheimer’s disease: linking molecular mechanisms of neurotoxicity, beta-amyloid biomarkers, and the diagnosis

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Potential Protective Function of Aβ₄₂ Monomer on Tauopathies