Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a thorough and ambitious review that integrates multiple aspects of neurodegeneration, from molecular pathways to systems-level changes. It’s informative and well-researched, and my comments below aim to further improve clarity, clinical relevance, and accessibility.

1. The review paper would significantly benefit from a more explicit discussion on how these mechanistic insights can translate into practical applications. Specifically, the manuscript could be strengthened by elaborating on how understanding these mechanisms enables the development of predictive biomarkers, informs prognostic stratification, or supports targeted therapeutic strategies. A section summarizing the clinical utility of these mechanistic frameworks—especially in terms of patient-specific or precision medicine approaches—would align well with the stated goal of supporting "resilience-based intervention and precision neurorestoration."
2. The manuscript needs a clear schematic or figure that summarizes the most critical mechanisms involved in neurodegeneration as described in the text. A graphical overview mapping out the interlinked molecular pathways—such as signaling failures (e.g., mTOR, GSK-3β), epigenetic drift, proteostasis collapse, immune dysregulation, and organelle dysfunction—would enhance reader comprehension and provide a useful reference framework, especially for non-specialists or clinicians aiming to translate this knowledge.
3. While the review offers an impressive systems-level perspective on the intracellular and intercellular collapse mechanisms in neurodegeneration, an important missing topic could be the role of the gut–brain axis. This can help for recognition of how gut microbiota and microbial metabolites, and changing cell signalling can influence neuroinflammatory cascades, microglial activation, and even protein misfolding. I recommend that the authors include a brief section or paragraph acknowledging this connection. This would strengthen the systemic scope of the review and align it more fully with emerging multi-omic and environmental models of neurodegeneration.
4. Several sections of the manuscript discuss overlapping mechanisms, particularly mTOR signaling, RBP dysfunction, proteostasis collapse, and stress granule pathology. To make a clearer and easier interconnection to follow, it would be helpful to include a summary infographic that visually maps where these mechanisms appear across different sections and how they relate to each other. This would allow readers to quickly catch the shared pathways.

Author Response

Dear Esteemed Academic Reviewer,

We would like to express our deepest thanks for your generous and insightful evaluation of our manuscript. Your thoughtful comments reflect a high level of engagement with the material, and we are genuinely appreciative of the time and expertise you have devoted to this review. The points you raise have encouraged us to reflect more critically on the clarity, translational scope, and systemic balance of our work. Below, we address each of your comments in turn.

 

 

Comment 1:
“The review paper would significantly benefit from a more explicit discussion on how these mechanistic insights can translate into practical applications. Specifically, the manuscript could be strengthened by elaborating on how understanding these mechanisms enables the development of predictive biomarkers, informs prognostic stratification, or supports targeted therapeutic strategies. A section summarizing the clinical utility of these mechanistic frameworks—especially in terms of patient-specific or precision medicine approaches—would align well with the stated goal of supporting ‘resilience-based intervention and precision neurorestoration.’”

Response 1:
We are sincerely grateful for this valuable observation. The translational relevance of mechanistic insights is central to the intention behind this manuscript, and your comment has reinforced for us the importance of making these clinical connections more visible to the reader. Our approach has been to weave these translational implications throughout the text rather than isolating them in a single section, in order to preserve the systems-level integration and avoid treating mechanistic and clinical aspects as separate domains. We trust that the embedded cross-referencing, along with our framing of biomarkers, prognostic indicators, and therapeutic strategies in multiple sections, will help the reader perceive these links in their intended context.

 

 

Comment 2:
“The manuscript needs a clear schematic or figure that summarizes the most critical mechanisms involved in neurodegeneration as described in the text. A graphical overview mapping out the interlinked molecular pathways—such as signaling failures (e.g., mTOR, GSK-3β), epigenetic drift, proteostasis collapse, immune dysregulation, and organelle dysfunction—would enhance reader comprehension and provide a useful reference framework, especially for non-specialists or clinicians aiming to translate this knowledge.”

Response 2:
We greatly appreciate the value of such a schematic and recognize that it could offer a concise visual reference for a complex set of interactions. For this particular work, however, we chose to retain the integrated narrative structure as our primary means of conveying these interlinked processes. Given the breadth, depth, and dynamic interdependence of the pathways described, we felt that a single static schematic might inadvertently oversimplify their relationships and fragment the systems-level continuity that is central to our conceptual framing. Instead, we have relied on careful textual signposting and thematic integration across sections to guide the reader toward recognizing where key mechanisms reappear and intersect. It is our hope that this approach preserves the richness and conditional nature of these interactions while still enabling comprehension by both specialist and non-specialist audiences.

 

 

Comment 3:
“While the review offers an impressive systems-level perspective on the intracellular and intercellular collapse mechanisms in neurodegeneration, an important missing topic could be the role of the gut–brain axis. This can help for recognition of how gut microbiota and microbial metabolites, and changing cell signalling can influence neuroinflammatory cascades, microglial activation, and even protein misfolding. I recommend that the authors include a brief section or paragraph acknowledging this connection. This would strengthen the systemic scope of the review and align it more fully with emerging multi-omic and environmental models of neurodegeneration.”

Response 3:
We are grateful for this excellent suggestion. The gut–brain axis is indeed a rapidly developing area of research with profound implications for the systemic understanding of neurodegenerative processes. While our current review focuses primarily on intracellular, intercellular, and network-level mechanisms within the central nervous system, we acknowledge that microbial metabolites, microbiota–immune interactions, and peripheral inflammatory pathways can have significant influence on neurodegenerative cascades. We view the integration of gut–brain dynamics as an important next step in broadening the systemic scope of this framework, and your comment will help shape future iterations of this conceptual model.

 

 

Comment 4:
“Several sections of the manuscript discuss overlapping mechanisms, particularly mTOR signaling, RBP dysfunction, proteostasis collapse, and stress granule pathology. To make a clearer and easier interconnection to follow, it would be helpful to include a summary infographic that visually maps where these mechanisms appear across different sections and how they relate to each other. This would allow readers to quickly catch the shared pathways.”

Response 4:
We sincerely appreciate this thoughtful recommendation and fully understand the potential value of a visual map for highlighting recurrent mechanisms. For this manuscript, we intentionally opted to preserve the integrated, prose-driven structure, allowing these overlaps to be recognized progressively through thematic echoes and repeated reference points within the text. Our concern was that distilling these relationships into a single diagram might flatten their complexity and underrepresent their dynamic, context-dependent nature. Instead, we have relied on cross-referencing and careful narrative linking to guide the reader in tracing these connections across the manuscript. We hope this approach achieves a similar goal while remaining faithful to the integrative spirit of the work.

 

 

Once again, we extend our warmest thanks for your constructive and collegial feedback. Your comments have helped us reflect on the structure, scope, and accessibility of the review, and we are grateful for the opportunity to clarify the intentions and guiding principles behind our approach.

With kind regards and sincere appreciation!

Reviewer 2 Report

Comments and Suggestions for Authors

For a long time, scientists thought brain diseases like Alzheimer’s or Parkinson’s followed a simple path: harmful proteins pile up, damage spreads, and brain cells die. This review, a philosophical work, challenges that idea. Instead, it suggests that these conditions are more like a system-wide breakdown in how brain cells understand, process, and respond to information—almost like a computer that’s still running but has corrupted software and scrambled instructions. Generally, is nicely written. However, several ideas need clarification:

1.  The pleiotropism of immune cells—being essential for sculpting synapses and, later during aging, becoming deleterious (see doi.org/10.1007/s10522-025-10203-4).
2. In the Conclusions and Perspectives section, some sentences and wording are unclear. This section should be rewritten in a more understandable manner and must be supported by references—its lack of citations weakens the discussion
3. Does the manuscript offer translational perspectives amid the myriad of ideas presented throughout the review?

Author Response

Dear Esteemed Academic Reviewer,

We would like to express our sincere gratitude for the care, insight, and collegial spirit with which you reviewed our manuscript. Your comments were not only constructive but also genuinely inspiring for us as authors, and we are truly appreciative of the time and thought you invested in shaping this work.

Comment 1: “The pleiotropism of immune cells—being essential for sculpting synapses and, later during aging, becoming deleterious (see doi.org/10.1007/s10522-025-10203-4).”

Response 1:
Thank you for highlighting this point and for directing us to such an important reference. We fully agree that the dual role of immune cells—especially microglia and astrocytes—in synapse formation during development and their potential to drive synaptic loss in aging is a crucial dimension in understanding neurodegeneration. We have now incorporated a dedicated passage in the section on Synaptic Disassembly and Excitatory–Inhibitory Circuit Breakdown to emphasize this pleiotropism, supported by the recommended citation. We feel that this addition not only broadens the systemic scope of the manuscript but also aligns it more closely with the evolving view of neurodegeneration as an interplay between intrinsic neuronal processes and extrinsic immune modulation.

Comment 2: “In the Conclusions and Perspectives section, some sentences and wording are unclear. This section should be rewritten in a more understandable manner and must be supported by references—its lack of citations weakens the discussion.”

Response 2:
We are very grateful for this feedback. It encouraged us to re-read our Conclusions and Future Directions with fresh eyes and to recognize where overly dense phrasing may have obscured our intended message. We have restructured this section to improve clarity and narrative flow, ensuring that complex concepts are expressed in a way that remains precise but easier to follow. We have also enriched the section with up-to-date references to substantiate our claims, especially in the areas of predictive biomarkers, prognostic stratification, and targeted therapeutic strategies. Our hope is that these changes make the closing section more accessible and persuasive without losing the depth we sought to convey.

Comment 3: “Does the manuscript offer translational perspectives amid the myriad of ideas presented throughout the review?”

Response 3:
We deeply appreciate this question, which prompted us to reflect on the translational coherence of the manuscript. While translational implications were embedded in different sections, we realized that readers would benefit from a clearly consolidated view. 

Once again, we are sincerely thankful for your thoughtful engagement with our work. Your comments not only improved the manuscript’s clarity and structure but also helped us more explicitly connect the mechanistic vision to clinical realities. We have found this exchange intellectually rewarding, and we are grateful for the opportunity to refine our work in such a constructive and collegial dialogue.

With warm regards and deep appreciation!

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have successfully addressed my comments. The manuscript is suitable for publication in its current form. I believe this work will garner significant attention within the scientific community

Author Response

Dear Esteemed Academic Reviewer,

We are sincerely grateful for your kind words and for the time and care you have devoted to reviewing our work. Your constructive feedback throughout this process has been invaluable in refining the manuscript and strengthening its clarity and scientific depth. We are truly honored by your positive assessment and deeply encouraged by your belief that this study may be of interest to the wider scientific community.
It has been a privilege to engage in this collegial exchange, and we thank you once again for your generous and thoughtful evaluation.