A dopamine metabolite stabilizes neurotoxic amyloid-β oligomers

Cataldi, Rodrigo; Chia, Sean; Pisani, Katarina; Ruggeri, Francesco Simone; Xu, Catherine K.; Šneideris, Tomas; Perni, Michele; Sarwat, Sunehera; Joshi, Priyanka; Kumita, Janet R.; Linse, Sara; Habchi, Johnny; Knowles, Tuomas P. J.; Mannini, Benedetta; Dobson, Christopher M.

doi:10.1038/s42003-020-01490-3

Cited by 35 publications

(29 citation statements)

References 81 publications

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“…These findings are in a good agreement with previously reported studies by Vendruscolo and Baskakov groups, which showed that oligomers have insignificant cell toxicity or exert substantially lower toxicity than fibrils. 49,51 ■ CONCLUSION Nanoscale IR analysis of Aβ 1−42 aggregates formed at different stages of aggregation revealed substantial complexity of these protein species. We found that Aβ first formed oligomers with parallel β-sheet structure that had much slower rates of fibril formation.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Nanoscale Characterization of Parallel and Antiparallel β-Sheet Amyloid Beta 1–42 Aggregates

Zhaliazka

Kurouski

2022

ACS Chem. Neurosci.

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Abrupt aggregation of amyloid beta (Aβ) peptide is strongly associated with Alzheimer's disease. In this study, we used atomic force microscopy−infrared (AFM-IR) spectroscopy to characterize the secondary structure of Aβ oligomers, protofibrils and fibrils formed at the early (4 h), middle (24 h), and late (72 h) stages of protein aggregation. This innovative spectroscopic approach allows for label-free nanoscale structural characterization of individual protein aggregates. Using AFM-IR, we found that at the early stage of protein aggregation, oligomers with parallel β-sheet dominated. However, these species exhibited slower rates of fibril formation compared to the oligomers with antiparallel β-sheet, which first appeared in the middle stage. These antiparallel β-sheet oligomers rapidly propagated into fibrils that were simultaneously observed together with parallel β-sheet fibrils at the late stage of protein aggregation. Our findings showed that aggregation of Aβ is a complex process that yields several distinctly different aggregates with dissimilar toxicities.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Nanoscale Characterization of Parallel and Antiparallel β-Sheet Amyloid Beta 1–42 Aggregates

Zhaliazka

Kurouski

2022

ACS Chem. Neurosci.

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“…Amyloid aggregates exert toxicities by enhancing ROS production and inducing mitochondrial dysfunction in cells [4,9]. To determine the extent to which Ins: DMPS, Ins:POPS, and Ins:DOPS engage ROS production and impair mitochondrial activity, we exposed these aggregates, as well as Ins to mice midbrain N27 cell line, Fig.…”

Section: Toxicity Of Insulin Aggregatesmentioning

confidence: 99%

“…In vitro experiments confirmed that denatured proteins can spontaneously self‐assemble forming aggregates with similar structures and morphologies as those observed in amyloid deposits. These experiments also reveal that a large number of biological molecules can uniquely alter rates of protein aggregation, as well as modify toxicity and secondary structure of fibrils [9–11]. For instance, Cataldi and co‐workers showed that 3,4‐dihydroxyphenylacetaldehyde, a product of dopamine oxidation, can uniquely change the secondary structure of amyloid β oligomers significantly increasing their toxicity [9].…”

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confidence: 99%

The degree of unsaturation of fatty acids in phosphatidylserine alters the rate of insulin aggregation and the structure and toxicity of amyloid aggregates

2022

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Phosphatidylserine (PS) in the plasma membrane plays an important role in cell signaling and apoptosis. Cell degeneration is also linked to numerous amyloid diseases, pathologies that are associated with aggregation of misfolded proteins. In this work, we examine the effect of both saturated PS (DMPS) and unsaturated PS (DOPS and POPS) on the aggregation properties of insulin, as well as the structure and toxicity of insulin aggregates formed in the presence of these phospholipids. We found that the degree of unsaturation of fatty acids in PS alters the rate of insulin aggregation. We also found that toxicity of insulin–DMPS aggregates is significantly lower than the toxicity of DOPS– and POPS–insulin fibrils, whereas all these lipid‐containing aggregates exert lower cell toxicity than insulin fibrils grown in a lipid‐free environment.

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“…The FNA approach prepares the oligomers by tethering the monomeric Aβ units inside a template 61 . A recent study by Cataldi et al 62 shows that a dopamine metabolite, 3,4‐dihydroxyphenylacetaldehyde, stabilizes dimers and trimers of Aβ40, which cause an enhancement in ROS production and induces the influx of Ca 2+ ions. The toxic effects of dimers, trimers, and the dodecamer/Aβ*56 are still under debate on which species is the most pathologically relevant.…”

Section: Characteristics Of Aβ Oligomersmentioning

confidence: 99%

Distinct types of amyloid‐β oligomers displaying diverse neurotoxicity mechanisms in Alzheimer's disease

Madhu

Mukhopadhyay

2021

J of Cellular Biochemistry

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Soluble oligomers of amyloid-β (Aβ) are recognized as key pernicious species in Alzheimer's disease (AD) that cause synaptic dysfunction and memory impairments. Numerous studies have identified various types of Aβ oligomers having heterogeneous peptide length, size distribution, structure, appearance, and toxicity. Here, we review the characteristics of soluble Aβ oligomers based on their morphology, size, and structural reactivity toward the conformationspecific antibodies and then describe their formation, localization, and cellular effects in AD brains, in vivo and in vitro. We also summarize the mechanistic pathways by which these soluble Aβ oligomers cause proteasomal impairment, calcium dyshomeostasis, inhibition of long-term potentiation, apoptosis, mitochondrial damage, and cognitive decline. These cellular events include three distinct molecular mechanisms: (i) high-affinity binding with the receptors for Aβ oligomers such as N-methyl-D-aspartate receptors, cellular prion protein, nerve growth factor, insulin receptors, and frizzled receptors; (ii) the interaction of Aβ oligomers with the lipid membranes; (iii) intraneuronal accumulation of Aβ by α7-nicotinic acetylcholine receptors, apolipoprotein E, and receptor for advanced glycation end products. These studies indicate that there is a pressing need to carefully examine the role of size, appearance, and the conformation of oligomers in identifying the specific mechanism of neurotoxicity that may uncover potential targets for designing AD therapeutics.

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A dopamine metabolite stabilizes neurotoxic amyloid-β oligomers

Cited by 35 publications

References 81 publications

Nanoscale Characterization of Parallel and Antiparallel β-Sheet Amyloid Beta 1–42 Aggregates

Nanoscale Characterization of Parallel and Antiparallel β-Sheet Amyloid Beta 1–42 Aggregates

The degree of unsaturation of fatty acids in phosphatidylserine alters the rate of insulin aggregation and the structure and toxicity of amyloid aggregates

Distinct types of amyloid‐β oligomers displaying diverse neurotoxicity mechanisms in Alzheimer's disease

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