Trodusquemine enhances Aβ                         42                          aggregation but suppresses its toxicity by displacing oligomers from cell membranes

Ryan Limbocker; Sean Chia; Francesco S. Ruggeri; Michele Perni; Roberta Cascella; Gabriella T. Heller; Georg Meisl; Benedetta Mannini; Johnny Habchi; Thomas C.T. Michaels; Pavan K. Challa; Minkoo Ahn; Samuel T. Casford; Nilumi Fernando; Catherine K. Xu; Nina D. Kloss; Samuel I.A. Cohen; Janet R. Kumita; Cristina Cecchi; Michael Zasloff; Sara Linse; Tuomas P.J. Knowles; Fabrizio Chiti; Michele Vendruscolo; Christopher M. Dobson

doi:10.1038/s41467-018-07699-5

Trodusquemine enhances Aβ ₄₂ aggregation but suppresses its toxicity by displacing oligomers from cell membranes

Ryan Limbocker
, Sean Chia
, Francesco S. Ruggeri
, Michele Perni
, Roberta Cascella
, Gabriella T. Heller
, Georg Meisl
, Benedetta Mannini
, Johnny Habchi
, Thomas C.T. Michaels
, Pavan K. Challa
, Minkoo Ahn
, Samuel T. Casford
, Nilumi Fernando
, Catherine K. Xu
, Nina D. Kloss
, Samuel I.A. Cohen
, Janet R. Kumita
, Cristina Cecchi
, Michael Zasloff

Sara Linse, Tuomas P.J. Knowles, Fabrizio Chiti, Michele Vendruscolo^*, Christopher M. Dobson

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

142 Citations (Scopus)

Abstract

Transient oligomeric species formed during the aggregation process of the 42-residue form of the amyloid-β peptide (Aβ ₄₂ ) are key pathogenic agents in Alzheimer’s disease (AD). To investigate the relationship between Aβ ₄₂ aggregation and its cytotoxicity and the influence of a potential drug on both phenomena, we have studied the effects of trodusquemine. This aminosterol enhances the rate of aggregation by promoting monomer-dependent secondary nucleation, but significantly reduces the toxicity of the resulting oligomers to neuroblastoma cells by inhibiting their binding to the cellular membranes. When administered to a C. elegans model of AD, we again observe an increase in aggregate formation alongside the suppression of Aβ ₄₂ -induced toxicity. In addition to oligomer displacement, the reduced toxicity could also point towards an increased rate of conversion of oligomers to less toxic fibrils. The ability of a small molecule to reduce the toxicity of oligomeric species represents a potential therapeutic strategy against AD.

Original language	English
Article number	225
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07699-5
Publication status	Published - 1 Dec 2019
Externally published	Yes

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Limbocker, R., Chia, S., Ruggeri, F. S., Perni, M., Cascella, R., Heller, G. T., Meisl, G., Mannini, B., Habchi, J., Michaels, T. C. T., Challa, P. K., Ahn, M., Casford, S. T., Fernando, N., Xu, C. K., Kloss, N. D., Cohen, S. I. A., Kumita, J. R., Cecchi, C., ... Dobson, C. M. (2019). Trodusquemine enhances Aβ ₄₂ aggregation but suppresses its toxicity by displacing oligomers from cell membranes. Nature Communications, 10(1), Article 225. https://doi.org/10.1038/s41467-018-07699-5

@article{ec82e34d968342bf9e2f494a661bd41f,

title = "Trodusquemine enhances Aβ 42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes",

abstract = " Transient oligomeric species formed during the aggregation process of the 42-residue form of the amyloid-β peptide (Aβ 42 ) are key pathogenic agents in Alzheimer{\textquoteright}s disease (AD). To investigate the relationship between Aβ 42 aggregation and its cytotoxicity and the influence of a potential drug on both phenomena, we have studied the effects of trodusquemine. This aminosterol enhances the rate of aggregation by promoting monomer-dependent secondary nucleation, but significantly reduces the toxicity of the resulting oligomers to neuroblastoma cells by inhibiting their binding to the cellular membranes. When administered to a C. elegans model of AD, we again observe an increase in aggregate formation alongside the suppression of Aβ 42 -induced toxicity. In addition to oligomer displacement, the reduced toxicity could also point towards an increased rate of conversion of oligomers to less toxic fibrils. The ability of a small molecule to reduce the toxicity of oligomeric species represents a potential therapeutic strategy against AD. ",

author = "Ryan Limbocker and Sean Chia and Ruggeri, \{Francesco S.\} and Michele Perni and Roberta Cascella and Heller, \{Gabriella T.\} and Georg Meisl and Benedetta Mannini and Johnny Habchi and Michaels, \{Thomas C.T.\} and Challa, \{Pavan K.\} and Minkoo Ahn and Casford, \{Samuel T.\} and Nilumi Fernando and Xu, \{Catherine K.\} and Kloss, \{Nina D.\} and Cohen, \{Samuel I.A.\} and Kumita, \{Janet R.\} and Cristina Cecchi and Michael Zasloff and Sara Linse and Knowles, \{Tuomas P.J.\} and Fabrizio Chiti and Michele Vendruscolo and Dobson, \{Christopher M.\}",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-018-07699-5",

language = "English",

volume = "10",

journal = "Nature Communications",

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Limbocker, R, Chia, S, Ruggeri, FS, Perni, M, Cascella, R, Heller, GT, Meisl, G, Mannini, B, Habchi, J, Michaels, TCT, Challa, PK, Ahn, M, Casford, ST, Fernando, N, Xu, CK, Kloss, ND, Cohen, SIA, Kumita, JR, Cecchi, C, Zasloff, M, Linse, S, Knowles, TPJ, Chiti, F, Vendruscolo, M & Dobson, CM 2019, 'Trodusquemine enhances Aβ ₄₂ aggregation but suppresses its toxicity by displacing oligomers from cell membranes', Nature Communications, vol. 10, no. 1, 225. https://doi.org/10.1038/s41467-018-07699-5

TY - JOUR

T1 - Trodusquemine enhances Aβ 42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes

AU - Limbocker, Ryan

AU - Chia, Sean

AU - Ruggeri, Francesco S.

AU - Perni, Michele

AU - Cascella, Roberta

AU - Heller, Gabriella T.

AU - Meisl, Georg

AU - Mannini, Benedetta

AU - Habchi, Johnny

AU - Michaels, Thomas C.T.

AU - Challa, Pavan K.

AU - Ahn, Minkoo

AU - Casford, Samuel T.

AU - Fernando, Nilumi

AU - Xu, Catherine K.

AU - Kloss, Nina D.

AU - Cohen, Samuel I.A.

AU - Kumita, Janet R.

AU - Cecchi, Cristina

AU - Zasloff, Michael

AU - Linse, Sara

AU - Knowles, Tuomas P.J.

AU - Chiti, Fabrizio

AU - Vendruscolo, Michele

AU - Dobson, Christopher M.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Transient oligomeric species formed during the aggregation process of the 42-residue form of the amyloid-β peptide (Aβ 42 ) are key pathogenic agents in Alzheimer’s disease (AD). To investigate the relationship between Aβ 42 aggregation and its cytotoxicity and the influence of a potential drug on both phenomena, we have studied the effects of trodusquemine. This aminosterol enhances the rate of aggregation by promoting monomer-dependent secondary nucleation, but significantly reduces the toxicity of the resulting oligomers to neuroblastoma cells by inhibiting their binding to the cellular membranes. When administered to a C. elegans model of AD, we again observe an increase in aggregate formation alongside the suppression of Aβ 42 -induced toxicity. In addition to oligomer displacement, the reduced toxicity could also point towards an increased rate of conversion of oligomers to less toxic fibrils. The ability of a small molecule to reduce the toxicity of oligomeric species represents a potential therapeutic strategy against AD.

AB - Transient oligomeric species formed during the aggregation process of the 42-residue form of the amyloid-β peptide (Aβ 42 ) are key pathogenic agents in Alzheimer’s disease (AD). To investigate the relationship between Aβ 42 aggregation and its cytotoxicity and the influence of a potential drug on both phenomena, we have studied the effects of trodusquemine. This aminosterol enhances the rate of aggregation by promoting monomer-dependent secondary nucleation, but significantly reduces the toxicity of the resulting oligomers to neuroblastoma cells by inhibiting their binding to the cellular membranes. When administered to a C. elegans model of AD, we again observe an increase in aggregate formation alongside the suppression of Aβ 42 -induced toxicity. In addition to oligomer displacement, the reduced toxicity could also point towards an increased rate of conversion of oligomers to less toxic fibrils. The ability of a small molecule to reduce the toxicity of oligomeric species represents a potential therapeutic strategy against AD.

U2 - 10.1038/s41467-018-07699-5

DO - 10.1038/s41467-018-07699-5

M3 - Article

C2 - 30644384

AN - SCOPUS:85060046863

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 225

ER -

Trodusquemine enhances Aβ 42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes

Abstract

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Trodusquemine enhances Aβ ₄₂ aggregation but suppresses its toxicity by displacing oligomers from cell membranes