Interaction of Aβ42 with Membranes Triggers the Self-Assembly into Oligomers
Round 1
Reviewer 1 Report
The authors deal with a very delicate and very complex topic The self-assembly of β (Aβ) amyloid proteins in oligomers is the main pathogenic event 11 which leads to Alzheimer's disease. Numerous studies have been conducted in particular on how to understand, starting for example from lysozyme, the membranes close, for example they could do studies with NMR or SANS technology to better complete their thesis supported by computer simulations. I would suggest aforementioned: Sancesario, G.M., Cencioni, M.T., Esposito, Z., Borsellino, G., Nuccetelli, M., Martorana, A., Battistini, L., (...), Sancesario, G. The load of amyloid-β oligomers is decreased in the cerebrospinal fluid of Alzheimer's disease patients(2012) Journal of Alzheimer's Disease, 31 (4), pp. 865-878. Cited 26 times.
www.iospress.nl/journal/journal-of-alzheimers-disease/
doi: 10.3233/JAD-2012-120211 Festa, G., Sancesario, G., Corsaro, C., Longo, S., Mallamace, D., Fazio, E., Arcidiacono, L., (...), Andreani, C. SANS study of Amyloid β1−40: Unfolded monomers in DMSO, multidimensional aggregates in water medium(2019) Physica A: Statistical Mechanics and its Applications, 517, pp. 385-391.
http://www.journals.elsevier.com/physica-a-statistical-mechanics-and-its-applications/
doi: 10.1016/j.physa.2018.11.027
Aggregation states of Aβ1-40, Aβ1-42 and Aβp3-42 amyloid beta peptides: A SANS study(Article)(Open Access) International Journal of Molecular Sciences Open AccessVolume 20, Issue 17, 1 September 2019, Article number 4126
Festa, G.,Mallamace, F.,Sancesario, G.M.,Corsaro, C.,Mallamace, D.,Fazio, E. Arcidiacono, L.,Sakai, V.G. Senesi, R.,Preziosi, E.,Sancesario, Andreani, C.
The work is well written and very fluid in the description.
In particular I would recommend figure 9 as a graphical abstract,
which I personally appreciated very much. Having made these small clarifications
and those small reference suggestions.
I believe that the work can be accepted after carrying out the required suggestions.
Author Response
Responses.
- According to the suggestions of the reviewer we have incorporated references showing the importance of oligomers in the disease development. Refs. 1-4 have been added to lines 27-30. One suggested reference was not accessible to us, thus we were not able to determine the relevance to the current paper.
- We have produced a ToC figure which show the key events described in the paper.
Reviewer 2 Report
The authors examined Aβ42 self-assembles into aggregates on membrane bilayers at low nanomolar concentrations. The results indicated that the interaction with membrane is the critical step towards Aβ42 oligomer formation at physiologically low protein concentration.
This is an important study focusing on the mechanisms of Aβ42 aggregation in physiological condition. As the process of misfolded protein aggregation is a crucial step in the pathophysiology of many neurodegenerative diseases, including Alzheimer’s disease, this manuscript will attract broad range of readers from basic researchers to physicians. The manuscript is well written.
Although I do not have any critical comments, minor suggestions to strengthen this manuscript are raised as follows:
Scientific interest of this manuscript is high. An issue regarding the significance of protein-membrane interaction and subsequent protein aggregation on tissue damage in other protein misfolding diseases will increase clinical interest. For example, transthyretin amyloidosis is a representative protein misfolding disease because the structure of causative protein has been well clarified and novel disease modifying therapies now appear one after another (Biomedicines 2019; 7: E11). I would recommend incorporating this issue in the beginning of the introduction section, citing this article.
“POPC” is spelled out at least twice in the text (Introduction and Materials and Methods sections). “Aβ42” is explained in the Materials and Methods, but not in the Introduction section. Please reconfirm the use of abbreviations in the text.
I would recommend including explanations for abbreviations (e.g., 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine for POPC in Figure 1 legend and table 1) in each figure legend and footnote of table.
Author Response
Responses:
- We have added abbreviations for amyloid b 42 in the main text, spelled out lipids and Abeta42 in figure legends, and added footnotes to Table 1.
- We have incorporated the suggested reference in lines 62-63, and included a short description on the transthyretin amyloidosis.
