Untangling Tau: Molecular Insights into Neuroinflammation, Pathophysiology, and Emerging Immunotherapies
, Philip Borsellino †, Keith Noorda, George Alhwayek and Thomas A. Vida *
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe manuscript addresses a significant and timely topic in the field of Alzheimer's Disease, focusing on the intricate relationship between neuroinflammation, tauopathies, and emerging immunotherapies. Overall, I find the paper to be a valuable contribution to the understanding of this complex subject. It offers a solid foundation for researchers and clinicians seeking insights into Alzheimer's Disease. However, I believe that some specific areas can be improved and expanded upon to enhance the comprehensiveness and clarity of the review.
- Risk Factors: While you've mentioned midlife risk factors, such as hypertension and diabetes, it would be helpful to briefly explain how these factors are linked to Alzheimer's Disease and the underlying mechanisms if space allows. This can provide readers with a deeper understanding of the disease's etiology.
- Genetic Predisposition: When discussing genetic predisposition, consider briefly explaining how mutations in amyloid precursor protein (APP), presenilin (PSEN1/2) genes, and allelic variation in apolipoprotein E (Apo E) are associated with Alzheimer's Disease. This will help readers unfamiliar with these terms.
- Neuroinflammation Introduction: While you introduce neuroinflammation well, it would be helpful to briefly explain how the immune response is triggered in the brain, mentioning key cytokines and signaling pathways involved in neuroinflammation. This can give readers a clearer understanding of the topic.
- Microglia and Astrocytes: The role of microglia and astrocytes in AD is well-described. However, it would be beneficial to include recent findings or developments in our understanding of these cells' functions in the context of neuroinflammation and Alzheimer's Disease. Are there any novel therapeutic strategies targeting microglia and astrocytes?
- Tauopathy and Neuroinflammation Connection: You discuss the relationship between neuroinflammation and AD, but it would be valuable to elaborate on how tauopathies, specifically the aggregation of tau protein, contribute to neuroinflammation. Do tau aggregates directly trigger neuroinflammatory responses, and if so, how?
- Tau Isoforms: While you provide information about tau isoforms, it might be worthwhile to clarify whether specific isoforms are more implicated in AD or if different isoforms have varying effects on disease progression.
- Tau Protein Domains: The section on tau protein domains is informative, but it would be enhanced by briefly explaining the functional significance of each domain and how post-translational modifications in these domains might contribute to tauopathy and neuroinflammation.
- Tau Oligomers: The section does a good job of highlighting the importance of tau oligomers. However, it would enhance the discussion to include recent studies or findings that support the pathological significance of tau oligomers and their role in neuronal damage and neurodegeneration.
- Tau Post-Translational Modifications (Section 3): The section provides a comprehensive overview of tau post-translational modifications, particularly phosphorylation and acetylation. However, it might be beneficial to emphasize the importance of site-specific modifications and their effects on tau function and aggregation.
- Immunotherapies: In the context of immunotherapies targeting tau phosphorylation, it would be valuable to mention any specific drugs or approaches that are currently under investigation or in clinical trials.
- Acetylation: The section on tau acetylation is informative, but it could benefit from a brief mention of how acetyl groups are added to lysine residues and how this process affects tau's function and structure.
- Balance with Phosphorylation: It's mentioned that acetylation plays a significant role in tauopathies, second only to phosphorylation. While this is intriguing, it would be helpful to explain how acetylation and phosphorylation interact or influence each other in the context of tau pathology.
- For each therapeutic intervention, provide a more in-depth discussion of the preclinical and clinical -evidence supporting its effectiveness. Discuss potential limitations and challenges associated with each approach.
- Consider including information on the current stage of development (e.g., clinical trial phases) for each therapeutic intervention to provide a sense of their potential clinical impact and timeline.
- After discussing each therapeutic intervention separately, consider providing a section or table that compares and evaluates these interventions based on various criteria, such as efficacy, safety, and current development status.
- Integration of Pathophysiological Mechanisms and Therapeutics: Connect the pathophysiological mechanisms discussed earlier in the paper with the respective therapeutic interventions. Explain how each intervention targets specific mechanisms or pathways. Consider adding subsections that explicitly link each therapeutic approach to the underlying pathophysiology it addresses.
- Clinical Relevance: Discuss the potential clinical implications of the various therapeutic interventions, including their suitability for different stages of disease progression and patient populations.
- Clarity of Information: The information about each antibody and its target epitope is clear and well-organized. However, consider adding a brief introduction to this section to provide context for the readers. Explain why these specific epitopes were chosen for targeting and their relevance in Alzheimer's disease.
- Mechanism of Action: Provide more detailed information on the mechanisms of action of these antibodies. How do they interact with tau proteins? How do they affect tau aggregation and propagation? This would provide a deeper understanding of their potential efficacy.
- Clinical Evidence: When discussing the effectiveness of these antibodies, provide specific clinical trial results, including any statistically significant findings. Mention if there were any limitations or challenges faced during the trials.
- Safety and Tolerance: While you mention safety and tolerance in clinical trials, elaborate on any adverse events observed and their significance. Discuss how these adverse events were managed or mitigated, if applicable.
- Future Directions: Expand on the future directions section. What are the potential challenges in developing tau immunotherapies, and how might they be addressed? Are there emerging technologies or approaches that could improve the effectiveness of these therapies?
Author Response
Please see the attachment.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsDear Authors,
I have read with interest the manuscript and I send you my comments:
1) Please add a section of methods were you explain the type of review and the methods of manuscript selection
2) The manuscript is of interest but it is not easy to read, please add tables in order to clarify the protein modification
3) Please add the risk factors able to modify the tau protein
4) Please add for each modification of tau protein, the clinical symptoms
Comments on the Quality of English Languagenone
Author Response
Please see the attachment.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsThe authors have addressed all of my suggested comments in a satisfactory manner. I am therefore pleased to recommend this manuscript for acceptance
Comments on the Quality of English Language.
Reviewer 2 Report
Comments and Suggestions for Authorsno comments
