The Role of Neuropeptide Y in the Pathogenesis of Alzheimer’s Disease: Diagnostic Significance and Neuroprotective Functions

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

 

Journal: Neurology International

Manuscript ID: neurolint-3261725

 

The manuscript title: “Role of neuropeptide Y in the pathogenesis of Alzheimer's disease: diagnostic significance and neuroprotective functions” by Ksenia Shapovalova et al, highlights the main ideas of the paper well, but it could need further clarification on the contradictions in the literature, greater focus on the mechanical function of NPY, and a more confident conclusion about the promise of NPY for both diagnosis and treatment.

By addressing these points, the manuscript would have more impact and scientific clarity.

 

1. The relationship between beta-amyloid and tau protein in neurodegenerative processes can be more clearly defined, highlight their role in neuronal damage and synaptic loss?

2. The involvement of glial cells in AD is noteworthy. Specifically, microglia and astrocytes are involved in neuroinflammation and plaque clearance, please cover these in the manuscript?

3.The manuscript introduces NPY's involvement without clearly explaining how it relates to AD pathogenesis or specifically. Give the further detail on the relationship involving neuropeptide imbalance and neurotoxicity?

 

 

NPY receptors

4. Give additional specific details about the roles played by the various NPY receptor subtypes (Y1, Y2, Y4, Y5) in distinct brain areas?

 

5. The first may bring up the role that NPY and its associated receptors play in neurological conditions such as Alzheimer's. more especially, how their dysfunction might result in issues with inflammatory conditions, synapse function, or neurological protection.

6. Although NPY's function in neurogenesis has been covered, more might be said about how it affects long-term potentiation and synaptic strength in terms of synaptic plasticity.

 

 

Results Section:

7. The section notes that the lowering of NPY levels in CSF has not been verified by other investigations, but it provides no explanation for why this may be the case. Talking about the technical difficulties in determining NPY, such as assay sensitivity, would be beneficial.

 

8. What causes alterations in NPY-expressing neurons in certain hippocampus subregions but not in others, and is there a connection between these variations in amyloid deposition, receptor distribution, or synaptic plasticity?

 

9. Furthermore, the various NPY receptor types (Y1, Y2, and Y5) involved in the protection should be properly distinguished from one another in the explanation of neuroprotective effects. Do these receptors function in concert or are they triggered differently in different parts of the brain?

 

Discussion:

10. It would be helpful to include a discussion of whether more recent omics techniques (proteomics, transcriptomics) or genetic research have shed light on NPY regulation in AD.

 

Table:

11. Table 1 (NPY levels in CSF and plasma) is helpful, but it is missing some crucial details, such the studies' standard deviations and mean NPY levels. An enhanced understanding of the variations seen in various research would result from the addition of statistical data.

12. Table 2 (NPY's neuroprotective qualities) is useful, but more details are required, such the amounts of NPY employed in these studies and the length of the treatments. It is difficult to evaluate the practical viability of NPY delivery in therapeutic settings without this knowledge.

 

Author Response

Dear Reviewer 1,

We are very grateful the Reviewer 1 for the taking the time and effort necessary to review our manuscript. We believe that Reviewer 1's suggestions and questions have made a significant contribution to improving our work, and we would like to express our gratitude for this important contribution. All the recommendations of this Reviewer 1 were implemented in the manuscript.

We would like to present our paper corrections in more understandable way. We have highlighted in yellow our addition in manuscript text. We hope that such form of answer will be appropriate. More detailed responses to comments are provided below.

 

Response to Reviewer 1 Comments:

 

1.

The manuscript title: “Role of neuropeptide Y in the pathogenesis of Alzheimer's disease: diagnostic significance and neuroprotective functions” by Ksenia Shapovalova et al, highlights the main ideas of the paper well, but it could need further clarification on the contradictions in the literature, greater focus on the mechanical function of NPY, and a more confident conclusion about the promise of NPY for both diagnosis and treatment.

Response: We thank Reviewer 1 for general comments on our manuscript. We have significantly added to or revised some sections of the manuscript, including the conclusion. We hope that this version of the manuscript will be more correct.

 

2.

By addressing these points, the manuscript would have more impact and scientific clarity.

1. The relationship between beta-amyloid and tau protein in neurodegenerative processes can be more clearly defined, highlight their role in neuronal damage and synaptic loss?
2. The involvement of glial cells in AD is noteworthy. Specifically, microglia and astrocytes are involved in neuroinflammation and plaque clearance, please cover these in the manuscript?

Response: We agree that this information is missing from the review, so we have elaborated on the topics you mentioned in the introduction of the review. We have described the mechanism of action of pathologic beta-amyloid and tau proteins in neurodegeneration and the consequences of this for neural tissue. In addition, the manuscript introduction is complemented by information on neuroinflammation in Alzheimer's disease and the role of glial cells in it.

 

3.

3.The manuscript introduces NPY's involvement without clearly explaining how it relates to AD pathogenesis or specifically. Give the further detail on the relationship involving neuropeptide imbalance and neurotoxicity?

Response: We agree with Reviewer 1's comment about the lack of information on pathologic mechanisms. Therefore, we have added more detailed information about the pathogenesis of Alzheimer's disease in relation to neuropeptide Y. Additionally, we have made a new illustration, with a schematic representation of the mechanisms (Figure 2).  In addition, we described new pathways of pathogenesis - autophagy and effects on BDNF expression, and described in more detail the mechanism through which neuropeptide Y reduces intracellular calcium concentration, which is a toxic factor in Alzheimer's disease pathology. These additions are summarized in section “3. Potential role of NPY in AD”.

 

4.

NPY receptors

4. Give additional specific details about the roles played by the various NPY receptor subtypes (Y1, Y2, Y4, Y5) in distinct brain areas?
5. The first may bring up the role that NPY and its associated receptors play in neurological conditions such as Alzheimer's. more especially, how their dysfunction might result in issues with inflammatory conditions, synapse function, or neurological protection.

Response: We thank Reviewer 1 for his attention to this issue and agree that more information on receptors and their relationship to neurodegeneration is needed. Therefore, we have considerably supplemented the section “2. NPY receptors”. We have emphasized the role of different receptor subtypes in brain function in normal and pathological conditions. We also described the role of neuropeptide Y and its receptors in connection with its neuroprotective function in neurodegenerative processes.

 

5.

6. Although NPY's function in neurogenesis has been covered, more might be said about how it affects long-term potentiation and synaptic strength in terms of synaptic plasticity.

Response: Although there is some information on the effect of neuropeptide Y on synaptic plasticity during stress and starvation and some other processes, its effect on synaptic plasticity during neurodegeneration remains unreported in the literature to date. Apparently, these properties of neuropeptide Y still need to be studied. Therefore, we decided not to address this topic in our review.

 

6.

Results Section:

7. The section notes that the lowering of NPY levels in CSF has not been verified by other investigations, but it provides no explanation for why this may be the case. Talking about the technical difficulties in determining NPY, such as assay sensitivity, would be beneficial.

Response: We fully agree that it is necessary to discuss the contradictions in studies concerning neuropeptide Y concentrations in blood and liquor, so we have supplemented the sections “5.1 NPY as diagnostic marker in CSF” and “5.2 NPY as diagnostic marker in blood plasma” with a discussion.

 

7.

8. What causes alterations in NPY-expressing neurons in certain hippocampus subregions but not in others, and is there a connection between these variations in amyloid deposition, receptor distribution, or synaptic plasticity?

Response: The authors of this study investigated neurogenesis in the Tg2576 mouse model of Alzheimer's disease. The study of NPY expression was not the main focus of this article. The authors in this article say that variations in the expression of NPY are known to reflect imbalances between excitatory and inhibitory neuronal activities in the hippocampus. However, the authors do not discuss amyloid and they have not investigated this relationship.  In general, the authors only suggest that, taken together, these data suggest that abnormal expression pattern of NPY in the hippo-campus of Tg2576 mice may reflect a compensatory inhibitory response to Aβ-induced aberrant excitatory neuronal activity. However, they do not test this assumption in this study.

 

8.

9. Furthermore, the various NPY receptor types (Y1, Y2, and Y5) involved in the protection should be properly distinguished from one another in the explanation of neuroprotective effects. Do these receptors function in concert or are they triggered differently in different parts of the brain?

Response: We have described the role of different neuropeptide Y receptor subtypes in neuroprotective function in section “2. NPY receptors” in conjunction with other receptor supplements.

 

9.

Discussion:

10. It would be helpful to include a discussion of whether more recent omics techniques (proteomics, transcriptomics) or genetic research have shed light on NPY regulation in AD.

Response: We are grateful to Reviewer 1 for this great idea to improve our manuscript and found some information on transcriptomics and GWAS, which we decided to include in the section “3. Potential role of NPY in AD”.

 

10.

Table:

11. Table 1(NPY levels in CSF and plasma) is helpful, but it is missing some crucial details, such the studies' standard deviations and mean NPY levels. An enhanced understanding of the variations seen in various research would result from the addition of statistical data.
12. Table 2(NPY's neuroprotective qualities) is useful, but more details are required, such the amounts of NPY employed in these studies and the length of the treatments. It is difficult to evaluate the practical viability of NPY delivery in therapeutic settings without this knowledge.

Response: We agree that Reviewer 1's suggested additions to the tables will be helpful to readers and are grateful for this excellent idea.  We have added specific statistical information on neuropeptide Y concentrations to Table 1. At the same time, we have supplemented Table 2 with available information on the amount and duration of drug administration.

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors,

While the review on the "Role of Neuropeptide Y in the Pathogenesis of Alzheimer's Disease: Diagnostic Significance and Neuroprotective Functions" addresses a topic of clear interest and relevance to the field, it is important to note that much of this subject has already been extensively covered in prior articles. Several of the mechanisms and implications discussed by the authors have been previously addressed in the literature. Furthermore, some areas require further attention to improve the manuscript's clarity and overall strength.

Major:

1) The authors did not specify the type of review conducted—was it systematic or narrative? Clarifying this would provide readers with a clearer understanding of the methodology used.

2) The authors should address the inconsistencies in the findings related to NPY levels in Alzheimer's disease patients. The current phrasing, "reduced or unchanged," is ambiguous and weakens the clarity of the conclusions. If conflicting results exist in the literature, the authors should explore potential reasons for these discrepancies, such as variations in sample sizes, experimental techniques, or patient cohorts. Simply stating that "these findings need to be confirmed" is insufficient without offering context or possible explanations for the variation.

3) The manuscript would benefit from a schematic model illustrating the potential pathways through which neuropeptide Y exerts its neuroprotective effects in Alzheimer's disease.

4) The review lacks a discussion on the relationship between NPY and autophagy. Given that both hypothalamic autophagy and NPY levels decrease with aging, and that NPY has been shown to regulate autophagy in the hypothalamus, this could represent a potential mechanism for delaying aging-related diseases. Incorporating this aspect would add valuable insight into the broader implications of NPY in aging and neurodegeneration.

5) It would also be worthwhile to note that, to date, NPY-related research has not yet been translated into clinical applications, likely due to challenges related to its mode of administration. A brief mention of these limitations would provide a balanced perspective and highlight the gap between experimental findings and therapeutic development.

6) Many of the references cited are somewhat outdated, which diminishes the review's impact and novelty. Incorporating more recent studies and findings would greatly enhance the manuscript and provide a more up-to-date perspective. 

Minor:

1) The figure description lacks information about its source and the graphical software used for its preparation.

2) In line 244, the authors have used terms in their native language without providing an English translation.

 

Author Response

Dear Reviewer 2,

We are very grateful the Reviewer 2 for analyzing our work and extremely helpful recommendations. The recommendations of Reviewer 2 really helped us to adjust our review considerably and to add very useful information that we had missed earlier.  We have tried to take into account all Reviewer 2's recommendations and corrected the text accordingly.

We would like to present our paper corrections in more understandable way. We have highlighted in yellow our addition in manuscript text. We hope that such form of answer will be appropriate. More detailed responses to comments are provided below.

 

Response to Reviewer 2 Comments:

 

1.

While the review on the "Role of Neuropeptide Y in the Pathogenesis of Alzheimer's Disease: Diagnostic Significance and Neuroprotective Functions" addresses a topic of clear interest and relevance to the field, it is important to note that much of this subject has already been extensively covered in prior articles. Several of the mechanisms and implications discussed by the authors have been previously addressed in the literature. Furthermore, some areas require further attention to improve the manuscript's clarity and overall strength.

Response: We thank Reviewer 2 for helpful comments on our review. Indeed, there are already reviews that address the topic of neuropeptide Y in various neurodegenerative diseases. However, in our review, we decided to summarize the information in more detail specifically for Alzheimer's disease. In addition, our review is the first to summarize information on Alzheimer's disease and neuropeptide Y in different directions - we considered the mechanisms of neuropeptide involvement in pathology, mechanisms of neuroprotection and potential diagnostic biomarkers. In addition, we have significantly updated the new version of the manuscript with useful information.

 

2.

• The authors did not specify the type of review conducted—was it systematic or narrative? Clarifying this would provide readers with a clearer understanding of the methodology used.

Response: We have performed a systematic literature search, in the section "4. Materials and Methods" we have indicated in detail how it was performed, and also now in this section we have additionally indicated that it is a systematic review. However, our review does not meet all Prisme criteria.

 

3.

• The authors should address the inconsistencies in the findings related to NPY levels in Alzheimer's disease patients. The current phrasing, "reduced or unchanged," is ambiguous and weakens the clarity of the conclusions. If conflicting results exist in the literature, the authors should explore potential reasons for these discrepancies, such as variations in sample sizes, experimental techniques, or patient cohorts. Simply stating that "these findings need to be confirmed" is insufficient without offering context or possible explanations for the variation.

Response: We fully agree that there is a need to discuss the controversy in studies concerning neuropeptide Y concentrations in blood and liquor, so we have supplemented the discussions with sections “5.1 NPY as diagnostic marker in CSF” and “5.2 NPY as diagnostic marker in blood plasma”. We described possible reasons for the discrepancies, such as differences in methods, small samples, or peculiarities of neuropeptide Y accumulation in liquor.

 

4.

• The manuscript would benefit from a schematic model illustrating the potential pathways through which neuropeptide Y exerts its neuroprotective effects in Alzheimer's disease.

Response: We thank Reviewer 2 for a great idea to improve the review. We have created a new illustration with the mechanisms of neuropeptide Y in neurodegeneration (Figure 2).

 

5.

• The review lacks a discussion on the relationship between NPY and autophagy. Given that both hypothalamic autophagy and NPY levels decrease with aging, and that NPY has been shown to regulate autophagy in the hypothalamus, this could represent a potential mechanism for delaying aging-related diseases. Incorporating this aspect would add valuable insight into the broader implications of NPY in aging and neurodegeneration.

Response: We are very grateful to you for mentioning such an important mechanism of cell defense against pathologically folded proteins. Previously we did not include this mechanism in the review, but we should have done so because it is very important. In addition, the effect of neuropeptide Y on autophagy remains poorly investigated at the moment; we found information about it from only one group of researchers. Therefore, describing this mechanism was very important for our review. We thank you again for this great idea, you have made a great contribution to show all mechanisms of neuropeptide Y in our review.  We have included a description of this important mechanism in chapter "3. Potential role of NPY in AD" and included this mechanism in Figure 2.

 

6.

• It would also be worthwhile to note that, to date, NPY-related research has not yet been translated into clinical applications, likely due to challenges related to its mode of administration. A brief mention of these limitations would provide a balanced perspective and highlight the gap between experimental findings and therapeutic development.

Response: We mentioned some clinical limitations about poor availability and permeability through the blood-brain barrier of neuropeptide in the conclusion. It should be noted, of course, that there is an intranasal route of administration of neuropeptide Y, which has been shown to be effective in clinical trials. However, there are few such studies and all these studies have dealt with other pathologies, mainly stress disorders and pain (e.g. Sayed S, Van Dam NT, Horn SR, et al. A Randomized Dose-Ranging Study of Neuropeptide Y in Patients with Posttraumatic Stress Disorder. Int J Neuropsychopharmacol. 2018;21(1):3-11. doi:10.1093/ijnp/pyx109). Unfortunately, no such studies have been conducted for Alzheimer's disease. We have written this review because we believe that neuropeptide Y may be useful for the therapy of Alzheimer's disease and therefore relevant studies are needed.

 

7.

• Many of the references cited are somewhat outdated, which diminishes the review's impact and novelty. Incorporating more recent studies and findings would greatly enhance the manuscript and provide a more up-to-date perspective. 

Response: We thank Reviewer 2 for bringing this issue to our attention. However, our review sought to cover all studies that describe neuropeptide Y in Alzheimer's disease. Unfortunately there are very few such studies, and some of them are really quite old, but we felt that they should be noted as well, since newer studies are not available.

 

8.

Minor:

1) The figure description lacks information about its source and the graphical software used for its preparation.

Response: We supplemented the figures with information about the way they were created: «The scientific image and illustration software BioRender.com was used to create the illustration».

 

9.

2) In line 244, the authors have used terms in their native language without providing an English translation.

Response: We thank you for finding and showing us this error, this text was unnecessary and we have removed it.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Journal: Neurology International (ISSN 2035-8377)

Manuscript ID: neurolint-3261725

 

I am pleased to inform you that your paper titled " Role of neuropeptide Y in the pathogenesis of Alzheimer's disease: diagnostic significance and neuroprotective functions " can be accepted in present form. We appreciate the diligent effort you put into addressing all the comments and feedback provided by the reviewers. Your thorough and thoughtful revisions have significantly enhanced the quality of the manuscript.

Thank you for your valuable contribution to the field.

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors,

I would like to thank you for your efforts in adapting the manuscript to the questions and concerns raised. You have provided comprehensive answers to all questions and suggestions. I am pleased to inform you that I recommend acceptance of the manuscript in its current form for publication in the Journal of Neurology International.

Best regards,