The Role of Oligodendrocytes in Alzheimer’s Disease Pathogenesis and Therapy
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsGuo and colleagues provided an outstanding summary of the oligodendrocytes, clearly outlining its key mechanisms, functions and related Alzheimer’s disease. Their explanation was both concise and comprehensive, making a complex topic accessible without oversimplifying it. By effectively highlighting the roles of oligodendrocytes, the various subtypes, and their physiological implications, Guo and colleagues created very nicely illustrated figures. Several pieces of new information presented here will certainly be referenced in my university lectures on the glial system. I read it with great interest — well done!
I recommend the acceptance of the manuscript, but I also suggest some minor comments that could further enhance the impact of the manuscript.
I have only some minor comments:
1, What role do gap junctions play in communication between oligodendrocytes themselves and in oligodendrocyte/astrocyte or oligodendrocyte–neuron communication? How much data is there about this?
2, As far as I know, cholesterol biosynthesis in the brain is under circadian control. Following this line of thought, what role do oligodendrocytes have or potentially have in sleep and the regulation of sleep?
3, In the Conclusions and Future Perspectives section, it may be worthwhile to briefly mention the relationship between oligodendrocytes and other neurodegenerative diseases.
4, It would be useful to briefly discuss single-cell RNA data from oligodendrocytes. This is a hot topic in science, and it would be very beneficial for readers. It could also potentially increase the importance of the manuscript.
Author Response
Comments from the Reviewer 1:
- What role do gap junctions play in communication between oligodendrocytes themselves and in oligodendrocyte/astrocyte or oligodendrocyte–neuron communication? How much data is there about this?
Response: We sincerely thank you for raising this insightful and essential question. We fully agree that elucidating the role of gap junctions in glial communication is crucial for a comprehensive understanding of oligodendrocyte biology and its implications in disease. To address this point directly, we have added an entirely new subsection, "1.5.5 Intercellular Communication via Gap Junctions" to our review manuscript. This subsection systematically elaborates on the specific roles of gap junctions in the three cellular communication scenarios you mentioned and assesses the strength of the existing evidence. The newly added text has been highlighted in red in the revised manuscript for your easy review.
- As far as I know, cholesterol biosynthesis in the brain is under circadian control. Following this line of thought, what role do oligodendrocytes have or potentially have in sleep and the regulation of sleep?
Response: Thank you for this insightful observation regarding the circadian control of cholesterol biosynthesis in the brain and its potential link to oligodendrocyte function in sleep regulation. We agree that this represents a critical and emerging area of research. In direct response to your comment, we have expanded the relevant discussion in the revised manuscript. Specifically, a new section has been added to the "Conclusions and Future Perspectives" that addresses the interconnected roles of oligodendrocytes in sleep regulation, circadian rhythms, and cholesterol metabolism, and how their dysregulation may influence AD pathogenesis. This addition is highlighted in red text for ease of review.
- In the Conclusions and Future Perspectives section, it may be worthwhile to briefly mention the relationship between oligodendrocytes and other neurodegenerative diseases.
Response: Thank you for this valuable suggestion. We agree that briefly highlighting the role of oligodendrocytes in other neurodegenerative diseases in the "Conclusions and Future Perspectives" section helps contextualize their broader significance and potential shared pathogenic mechanisms. Accordingly, we have added a concise paragraph in that section. It now summarizes the distinct yet convergent roles of oligodendrocyte dysfunction—such as immune-mediated demyelination in MS, α-synuclein aggregation in MSA, and genetic risk/microenvironment alterations in PD—and emphasizes how insights from these disorders can inform our understanding of oligodendrocyte involvement in AD pathogenesis and therapeutic strategies. This addition has been incorporated into the revised manuscript, and the relevant text is highlighted in red.
- It would be useful to briefly discuss single-cell RNA data from oligodendrocytes. This is a hot topic in science, and it would be very beneficial for readers. It could also potentially increase the importance of the manuscript.
Response: Thank you for raising this highly relevant and valuable point. We agree that incorporating insights from single-cell RNA sequencing (scRNA-seq) studies is essential for understanding oligodendrocyte heterogeneity and their state-specific alterations in Alzheimer’s disease (AD). In response to this suggestion, we have added a brief discussion in the "Conclusions and Future Perspectives" of the revised manuscript that highlights key findings from recent scRNA-seq studies on oligodendrocyte lineage cells in AD. This includes mentions of disease-associated oligodendrocyte states, transcriptional shifts related to lipid metabolism and stress responses, and the identification of oligodendrocyte subpopulations that may contribute to neuroinflammation or myelin dysfunction. This addition strengthens the mechanistic discussion of oligodendrocyte involvement in AD and aligns the review with current advances in the field. The added content is included in the relevant section and is highlighted in red for convenience.
Reviewer 2 Report
Comments and Suggestions for AuthorsIn this review, the authors have explored the various roles of oligodendrocytes in the pathogenesis of Alzheimer's disease. Considering that this research area is of current interest, this review is timely.
Overall, this review is very well written, with clear diagrams that enhanced the understanding of the subject. The layout is logical, with the authors first providing a detailed background on oligodendrocyte physiology, followed by a discussion on its contributions to Alzheimer's disease and speculations on potential therapeutics that could be emerged from these knowledge.
Just a few suggestions:
1) It would be useful to include more references published within the last five years.
2) While the authors have outlined the various roles oligodendrocytes played in the pathogenesis of Alzheimer's disease in terms of Aß amyloid plaques/ Tau neurofibrillary tangles, can the authors comment on functional/pathophysiological/morphological differences between oligodendrocytes in normal brains and those in AD brains?
3) While this is potentially beyond the scope of the topic, can the authors comment on the role of oligodendrocytes in other neurodegenerative diseases, and any similarities to AD?
Author Response
- It would be useful to include more references published within the last five years.
Response: Thank you for this constructive suggestion. We agree that incorporating the most recent literature is crucial for a timely review. In response, we have systematically re-examined the reference list throughout the manuscript and, where possible, updated it by replacing older citations with key studies published within the last five years. We believe this revision has enhanced the article's timeliness and relevance.
- While the authors have outlined the various roles oligodendrocytes played in the pathogenesis of Alzheimer's disease in terms of Aß amyloid plaques/ Tau neurofibrillary tangles, can the authors comment on functional/pathophysiological/morphological differences between oligodendrocytes in normal brains and those in AD brains?
Response: Thank you for the suggestion. In response, we have added a summary comparing the functional, pathophysiological, and morphological features of oligodendrocytes in normal vs. AD brains in the "Conclusions and Future Perspectives" section, which is now highlighted in red in the revised manuscript.
- While this is potentially beyond the scope of the topic, can the authors comment on the role of oligodendrocytes in other neurodegenerative diseases, and any similarities to AD?
Response: Thank you for raising this insightful question regarding the broader relevance of oligodendrocyte dysfunction. In response to this comment, we have added a concise discussion of this point in the "Conclusions and Future Perspectives" section. This addition briefly outlines the roles of oligodendrocytes in other major neurodegenerative diseases, such as multiple sclerosis, multiple system atrophy, and Parkinson's disease. It highlights both convergent and disease-specific mechanisms compared to Alzheimer's disease. To facilitate review, the newly added text has been highlighted in red in the revised manuscript.
