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A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers.

Cohen SI, Arosio P, Presto J, Kurudenkandy FR, Biverstål H, Dolfe L, Dunning C, Yang X, Frohm B, Vendruscolo M, Johansson J, Dobson CM, Fisahn A, Knowles TP, Linse S - Nat. Struct. Mol. Biol. (2015)

Bottom Line: Recent studies have revealed that once Aβ42 fibrils are generated, their surfaces effectively catalyze the formation of neurotoxic oligomers.We demonstrate in vitro that Brichos achieves this inhibition by binding to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves minimal formation of toxic oligomeric intermediates.These results reveal that molecular chaperones can help maintain protein homeostasis by selectively suppressing critical microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Cambridge, Cambridge, UK.

ABSTRACT
Alzheimer's disease is an increasingly prevalent neurodegenerative disorder whose pathogenesis has been associated with aggregation of the amyloid-β peptide (Aβ42). Recent studies have revealed that once Aβ42 fibrils are generated, their surfaces effectively catalyze the formation of neurotoxic oligomers. Here we show that a molecular chaperone, a human Brichos domain, can specifically inhibit this catalytic cycle and limit human Aβ42 toxicity. We demonstrate in vitro that Brichos achieves this inhibition by binding to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves minimal formation of toxic oligomeric intermediates. We verify that this mechanism occurs in living mouse brain tissue by cytotoxicity and electrophysiology experiments. These results reveal that molecular chaperones can help maintain protein homeostasis by selectively suppressing critical microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation.

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Brichos reduces the toxicity associated with the aggregation of Aβ42 in brain slices(a) Solutions containing mature fibrils alone and chaperone alone do not show increased toxicity relative to the control (first gray bar, p = 0.3 and p = 0.5). The toxicity is, however, increased relative to the control for solutions (Δt = 15 min) undergoing aggregation from initially purely monomeric peptide (orange bar, p = 0.02, indicated *), and is furthermore dramatically increased in samples initially containing monomeric Aβ42 with pre-formed fibrils (red bar, p < 0.0001, indicated ***). In both of these aggregation reactions, the toxicity is strongly suppressed to a level comparable with the control by adding Brichos in solution (green bars, p = 0.3 and p = 0.2 relative to the control). The box-and-whisker plot is based on 8-16 repeats for each condition as indicated, with the boxes enclosing data from the first to the third quartile, the horizontal line being drawn at the median, the whiskers indicating the range, and the number of repeats given above or below. All p-values are based on two-tailed Mann-Whitney U-tests relative to the control. (b) Representative traces and power spectra of the kainate-induced gamma oscillation measurements for the control (gray), the monomeric peptide (orange) and the monomeric peptide supplemented with pre-formed fibrils (red).
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Figure 5: Brichos reduces the toxicity associated with the aggregation of Aβ42 in brain slices(a) Solutions containing mature fibrils alone and chaperone alone do not show increased toxicity relative to the control (first gray bar, p = 0.3 and p = 0.5). The toxicity is, however, increased relative to the control for solutions (Δt = 15 min) undergoing aggregation from initially purely monomeric peptide (orange bar, p = 0.02, indicated *), and is furthermore dramatically increased in samples initially containing monomeric Aβ42 with pre-formed fibrils (red bar, p < 0.0001, indicated ***). In both of these aggregation reactions, the toxicity is strongly suppressed to a level comparable with the control by adding Brichos in solution (green bars, p = 0.3 and p = 0.2 relative to the control). The box-and-whisker plot is based on 8-16 repeats for each condition as indicated, with the boxes enclosing data from the first to the third quartile, the horizontal line being drawn at the median, the whiskers indicating the range, and the number of repeats given above or below. All p-values are based on two-tailed Mann-Whitney U-tests relative to the control. (b) Representative traces and power spectra of the kainate-induced gamma oscillation measurements for the control (gray), the monomeric peptide (orange) and the monomeric peptide supplemented with pre-formed fibrils (red).

Mentions: We next analyzed whether or not the reduction in the population of oligomeric species resulting from the specific suppression of the secondary nucleation pathway by Brichos can be sufficient to reduce the high level of neurotoxicity associated with Aβ42 aggregation in brain tissue. To this effect, we used electrophysiology techniques on mouse brain slices to measure the degree of Aβ42-induced impairment of hippocampal gamma oscillations in the presence and absence of Brichos (Fig. 5). Gamma oscillations are important for higher brain functions such as cognition, learning and memory, and are found to be degraded in brain disorders that lead to cognitive decline in patients suffering from neurodegenerative disorders such as Alzheimer’s disease52.


A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers.

Cohen SI, Arosio P, Presto J, Kurudenkandy FR, Biverstål H, Dolfe L, Dunning C, Yang X, Frohm B, Vendruscolo M, Johansson J, Dobson CM, Fisahn A, Knowles TP, Linse S - Nat. Struct. Mol. Biol. (2015)

Brichos reduces the toxicity associated with the aggregation of Aβ42 in brain slices(a) Solutions containing mature fibrils alone and chaperone alone do not show increased toxicity relative to the control (first gray bar, p = 0.3 and p = 0.5). The toxicity is, however, increased relative to the control for solutions (Δt = 15 min) undergoing aggregation from initially purely monomeric peptide (orange bar, p = 0.02, indicated *), and is furthermore dramatically increased in samples initially containing monomeric Aβ42 with pre-formed fibrils (red bar, p < 0.0001, indicated ***). In both of these aggregation reactions, the toxicity is strongly suppressed to a level comparable with the control by adding Brichos in solution (green bars, p = 0.3 and p = 0.2 relative to the control). The box-and-whisker plot is based on 8-16 repeats for each condition as indicated, with the boxes enclosing data from the first to the third quartile, the horizontal line being drawn at the median, the whiskers indicating the range, and the number of repeats given above or below. All p-values are based on two-tailed Mann-Whitney U-tests relative to the control. (b) Representative traces and power spectra of the kainate-induced gamma oscillation measurements for the control (gray), the monomeric peptide (orange) and the monomeric peptide supplemented with pre-formed fibrils (red).
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Related In: Results  -  Collection

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Figure 5: Brichos reduces the toxicity associated with the aggregation of Aβ42 in brain slices(a) Solutions containing mature fibrils alone and chaperone alone do not show increased toxicity relative to the control (first gray bar, p = 0.3 and p = 0.5). The toxicity is, however, increased relative to the control for solutions (Δt = 15 min) undergoing aggregation from initially purely monomeric peptide (orange bar, p = 0.02, indicated *), and is furthermore dramatically increased in samples initially containing monomeric Aβ42 with pre-formed fibrils (red bar, p < 0.0001, indicated ***). In both of these aggregation reactions, the toxicity is strongly suppressed to a level comparable with the control by adding Brichos in solution (green bars, p = 0.3 and p = 0.2 relative to the control). The box-and-whisker plot is based on 8-16 repeats for each condition as indicated, with the boxes enclosing data from the first to the third quartile, the horizontal line being drawn at the median, the whiskers indicating the range, and the number of repeats given above or below. All p-values are based on two-tailed Mann-Whitney U-tests relative to the control. (b) Representative traces and power spectra of the kainate-induced gamma oscillation measurements for the control (gray), the monomeric peptide (orange) and the monomeric peptide supplemented with pre-formed fibrils (red).
Mentions: We next analyzed whether or not the reduction in the population of oligomeric species resulting from the specific suppression of the secondary nucleation pathway by Brichos can be sufficient to reduce the high level of neurotoxicity associated with Aβ42 aggregation in brain tissue. To this effect, we used electrophysiology techniques on mouse brain slices to measure the degree of Aβ42-induced impairment of hippocampal gamma oscillations in the presence and absence of Brichos (Fig. 5). Gamma oscillations are important for higher brain functions such as cognition, learning and memory, and are found to be degraded in brain disorders that lead to cognitive decline in patients suffering from neurodegenerative disorders such as Alzheimer’s disease52.

Bottom Line: Recent studies have revealed that once Aβ42 fibrils are generated, their surfaces effectively catalyze the formation of neurotoxic oligomers.We demonstrate in vitro that Brichos achieves this inhibition by binding to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves minimal formation of toxic oligomeric intermediates.These results reveal that molecular chaperones can help maintain protein homeostasis by selectively suppressing critical microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Cambridge, Cambridge, UK.

ABSTRACT
Alzheimer's disease is an increasingly prevalent neurodegenerative disorder whose pathogenesis has been associated with aggregation of the amyloid-β peptide (Aβ42). Recent studies have revealed that once Aβ42 fibrils are generated, their surfaces effectively catalyze the formation of neurotoxic oligomers. Here we show that a molecular chaperone, a human Brichos domain, can specifically inhibit this catalytic cycle and limit human Aβ42 toxicity. We demonstrate in vitro that Brichos achieves this inhibition by binding to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves minimal formation of toxic oligomeric intermediates. We verify that this mechanism occurs in living mouse brain tissue by cytotoxicity and electrophysiology experiments. These results reveal that molecular chaperones can help maintain protein homeostasis by selectively suppressing critical microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation.

Show MeSH
Related in: MedlinePlus