From the journal RSC Chemical Biology Peer review history

02-Mar-2024

Dear Dr Matsubara:

Manuscript ID: CB-ART-02-2024-000038
TITLE: Prevention of amyloid β fibrils deposition on the synaptic membrane in the precuneus by ganglioside nanocluster-targeting inhibitors

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Claudia Höbartner
Associate Editor, RSC Chemical Biology
Institute of Organic Chemistry, University of Würzburg

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Reviewer 1

This manuscript (Miyamoto, E, et al) is a revised version of the manuscript submitted to ChemComm. Its authors made sufficient revisions in response to reviewers’ comments. It provides more significance and impact than its earlier version. It is strongly recommended for publication in RSC Chem Biol.

Reviewer 2

The here revised manuscript describes a thorough investigation on amyloid-aggregation on precisely engineered surfaces under action of a peptidic inhibitor. It is addressing the issue of raft-based nucleation of Abeta; linked to biomembranes(synaptic) and the demonstration of an inhibiting peptide. The study, already revised once, is well conducted, and - although focussed on a model system - well demonstrates that such effects can be significant for in vivo systems as well. The manuscript is well composed, and merits publication.
I see that a lot of work has been spent on (a) careful membrane reconsitution (b) meeting a good characterization by AFM and (c) relating the fibrillization to the surface sciences. I understand that fibril counting is required to nail down the quantitiy of fibril-association, but a more detailed description as to the relation to "the 3dimensional world of fibrillation" wuld be more than welcome. It serves to better understand the significance of the assays used here.

I recommend also to polish the newly added parts, especially the one on page Nr 5, red parts on the bottom : they are not language pefect, and not fully clear.

This text has been copied from the PDF response to reviewers and does not include any figures, images or special characters.

This manuscript (Manuscript ID: CB-ART-02-2024-000038) is a revised version according to the reviewer's comments. Our responses to the reviewers' comments are attached below for your convenience. A marked-up (red portions) manuscript is also attached.

To Editor
- Responding to reviewer 2's comments, all parts marked in red have been revised by proofreading service.

To Reviewer #2
(Query #2) I recommend also to polish the newly added parts, especially the one on page 5, red parts on the bottom; they are not language perfect, and not fully clear.

(Reply #2) We are grateful this comment. The following statements on page 5 have been revised by proofreading service (Cactus Communications Co. Ltd.).

Original Manuscript
Proposed model for clearance of Aβ assembly on synaptic membrane by ganglioside nanocluster-targeting inhibitors

Our results indicated that the reconstituted membrane composed of SPM lipids mimics synaptic membrane and induces toxic Aβ fibrils through GAβ complex (Figure 8). Although the SPM lipids contains multiple gangliosides, Aβ assemblies observed in this study were similar to those on GM1- and other gangliosidecontaining membranes reported in previous papers.28 These Aβ assemblies have possibility for taking β-sheet structures, but not determined in the present stage.23, 27 Information of secondary structures of Aβ assemblies induced by ganglioside nanocluster is limited, further structural investigation should be performed in this field. In addition, the binding of GCBP and cy5A to the membrane with PC lipids specifically inhibited Aβ fibril formation and promoted the release of Aβ42 assemblies. Disruption of GAβ complex by binding of peptide inhibitors to ganglioside nanocluster is one of the promising mechanism of these effects to reduce Aβ deposition as reported previously.42,43

Natural products of various polyphenols containing tannic acid, curcumin, and epigallocatechin-3-gallate have inhibition capacity with IC50 values of 0.012–27 μM for Aβ aggregation in vitro.44 In previous studies, GCBP and cy5A have been shown to inhibit GM1-induced Aβ aggregation with IC50 values of 12 pM and 1.2 fM, respectively.42,43 Alanine scanning result shows arginines (Arg3, Arg12) and hydrophobic amino acids (Trp3, Phe9) of GCBP and cy5A interact with sialic acid and galactose ring of gangliosides.17 Although several kinds of gangliosides in the SPM lipids should be involved in Aβ fibril formation, it is possible to design promising inhibitors, based on our peptides, against ganglioside-induced Aβ assembly.

Revised version (marked in yellow)
Proposed model for the clearance of Aβ assembly on synaptic membranes by ganglioside nanocluster-targeting inhibitors

Our results indicated that the reconstituted membrane composed of SPM lipids mimics the synaptic membrane and induces toxic Aβ fibrils through the GAβ complex (Figure 8). Although SPM lipids contain multiple gangliosides, Aβ assemblies observed in this study were similar to those on GM1- and other ganglioside-containing membranes reported in previous papers.28 These Aβ assemblies have the potential to take β-sheet structures, but this has not been determined in the present stage.23, 27 Information on secondary structures of Aβ assemblies induced by ganglioside nanoclusters is limited, and further structural investigations are needed. In addition, the binding of GCBP and cy5A to the membrane with PC lipids specifically inhibited Aβ fibril formation and promoted the release of Aβ42
assemblies. Disruption of the GAβ complex by the binding of peptide inhibitors to ganglioside nanoclusters is a promising mechanism to reduce Aβ deposition, as reported previously.42,43

Natural products of various polyphenols containing tannic acid, curcumin, and epigallocatechin-3-gallate have inhibitory effects, with IC50 values of 0.012–27 μM for Aβ aggregation in vitro.44 In previous studies, GCBP and cy5A have been shown to inhibit GM1-induced Aβ aggregation with IC50 values of 12 pM and 1.2 fM, respectively.42, 43 Alanine scanning has revealed that arginines (Arg3 and Arg12) and hydrophobic amino acids (Trp3 and Phe9) of GCBP and cy5A interact with sialic acid and the galactose ring of gangliosides.17 Although several kinds of gangliosides in SPM lipids likely contribute to Aβ fibril formation, the design of inhibitors, based on our peptides, against ganglioside-induced Aβ assembly, is a promising strategy.

16-Mar-2024

Dear Dr Matsubara:

Manuscript ID: CB-ART-02-2024-000038.R1
TITLE: Prevention of amyloid β fibrils deposition on the synaptic membrane in the precuneus by ganglioside nanocluster-targeting inhibitors

Thank you for submitting your revised manuscript to RSC Chemical Biology. I am pleased to accept your manuscript for publication in its current form.

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Claudia Höbartner
Associate Editor, RSC Chemical Biology


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