PONE-D-21-15019

NNC 26-9100 Increases Aβ1-42 Phagocytosis, Inhibits Nitric Oxide Production and Decreases Calcium in BV2 Microglia Cells

PLOS ONE

Dear Dr. Schober,

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Two experts have seen the manuscript and only asked for minor changes, as detailed in their reviews. Modifications should include justification for the agonist concentrations used in different experiments, addition of abbreviations and further explanations regarding the therapeutic importance of the study.

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Academic Editor

PLOS ONE

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5.  Thank you for stating the following in the Competing Interests section:

Authors K. Witt, A. Crider, and K. Sandoval are co-inventors on patent applications for the development of SSTR4 agonists, through Southern Illinois University Edwardsville (USA patent application No. PCT/US2018/032368; European National Application No. 18798793.8, Japanese Application No. 2019-562574). Ken Witt is CEO of Somatolynk Inc, a company focused on advancement of SST4 agonists.

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The National Institute on Aging of the National Institutes of Health award number R01AG047858 and SIUE Research Grants for Graduate Students supported this research.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript examines the effect on SST4 receptor agonist NNC 26-9100 on BV2 microglia cells with special focus on cell function related to Alzheimer’s disease. The design of the study is elaborate. Methods are modern and English language is excellent. I have two minor questions:

Why is the maximal concentration of NNC 26-9100 different in Alamar blue, LDH and nitrite assays compared to the other experiments?

They authors conclude on shift of microglia to M2 phenotype. This should only be included if respective cell markers are examined and phenotype shift can be objectively demonstrated.

Reviewer #2: The well-written manuscript of Schober and co-authors presents a nice and thorough work, analysing the effects of an SSTR4 agonist on microglia function. The Authors confirmed that NNC Is able to decrease the LPS-induced lactate dehydrogenase and nitrite release, while in the absence of LPS, increase Aβ uptake. The data presented in this manuscript confirm the previous results of the Authors. In my opinion the results are clear and well-described, only few modifications are needed:

The explanations of some abbreviations are missing from the manuscript (SSTR4, SRIF).

The article would greatly benefit from a brief description of the role of SSRTs and SRIF in AD, to emphasize the potential therapeutic applicability of the results.

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Reviewer #1: No

Reviewer #2: No

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NNC 26-9100 Increases Aβ1-42 Phagocytosis, Inhibits Nitric Oxide Production and Decreases Calcium in BV2 Microglia Cells

PONE-D-21-15019R1

Dear Dr. Schober,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Mária A. Deli, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: (No Response)

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: (No Response)

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: (No Response)

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: (No Response)

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors answered all of my questions. The already high quality paper has been corrected even further. The paper is now suitable for publication.

Reviewer #2: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Dr. Gabor Pozsgai

Reviewer #2: No