Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review provides a comprehensive and timely overview of the intricate relationship between post-translational modifications (PTMs), the protein quality control (PQC) system, and the pathogenesis of Alzheimer’s disease (AD). The manuscript successfully synthesizes a large body of literature, moving beyond the traditional amyloid cascade to argue for a more holistic, systems-level view of proteostasis failure in AD. The figures and tables are informative, and the discussion of PTM cross-talk and PQC exhaustion is a particular strength. However, the manuscript requires significant revisions to improve clarity, correct redundancies, address minor inaccuracies.

1.The core argument—that PTMs and PQC failure form a synergistic, self-perpetuating cycle in AD—is compelling and clinically relevant.

2.The manuscript is currently too long, with significant redundancy between general background sections and the disease-specific sections.

3.The discussion of future therapeutic strategies lacks sufficient specificity.

4.Several sentences are overly long and complex (e.g., page 8, lines 350-360 on PTM cross-talk). Break these into shorter, clearer statements.

Author Response

Reviewer 1

This review provides a comprehensive and timely overview of the intricate relationship between post-translational modifications (PTMs), the protein quality control (PQC) system, and the pathogenesis of Alzheimer’s disease (AD). The manuscript successfully synthesizes a large body of literature, moving beyond the traditional amyloid cascade to argue for a more holistic, systems-level view of proteostasis failure in AD. The figures and tables are informative, and the discussion of PTM cross-talk and PQC exhaustion is a particular strength. However, the manuscript requires significant revisions to improve clarity, correct redundancies, address minor inaccuracies.

 

1.The core argument—that PTMs and PQC failure form a synergistic, self-perpetuating cycle in AD—is compelling and clinically relevant.

Response: We thank the reviewer for the comment.

2.The manuscript is currently too long, with significant redundancy between general background sections and the disease-specific sections.

Response: According to the reviewer’s suggestion, we have removed all the redundancy from the manuscript, especially focusing on general background sections and the disease-specific sections.

3.The discussion of future therapeutic strategies lacks sufficient specificity.

Response: We thank the reviewer for the comment. In the revised manuscript, we discussed the future therapeutic strategy of AD (Section 7)

4.Several sentences are overly long and complex (e.g., page 8, lines 350-360 on PTM cross-talk). Break these into shorter, clearer statements.

Response: We tried to use more simple sentences.

Reviewer 2 Report

Comments and Suggestions for Authors

I recommend the manuscript for major revision, as it requires several substantial improvements in its current form.

Comments for author File: Comments.pdf

Author Response

Reviewer 2

This manuscript provides a comprehensive overview of post-translational modifications and protein quality control systems in Alzheimer’s disease. However, the review is largely descriptive and lacks critical analysis and conceptual novelty. 

Response: We thank the reviewer for the comment. In the revised manuscript, we tried to improve the explanation and implications of the recent advances of the role of PTMs and PQCs in AD pathology. Also, we discussed how PQC and PTM can be included in more effective AD therapies.

Major comments 

1. The manuscript provides a broad overview of post-translational modifications (PTMs) and protein quality control (PQC) systems in Alzheimer’s disease. However, the discussion remains largely descriptive. The authors summarize existing knowledge without sufficiently addressing conflicting findings, unresolved questions, or alternative mechanistic interpretations. In particular, the interplay between PTMs and PQC is presented in a generalized manner, lacking deeper mechanistic insight and critical evaluation of causality versus consequence.  Strengthening the analytical component would significantly improve the scientific value of the review.  Specifically, I encourage authors to critically compare competing hypotheses, address contradictions in the literature, and clearly distinguish the causal and consequential roles of post-translational modifications (PTMs) and post-translational control (PQC) dysfunction in Alzheimer’s disease. Furthermore, the depth and impact of the manuscript would be enhanced if the authors discussed in greater detail and more integratively how specific PTMs influence PQC pathways (and vice versa). 

Response: In the revised manuscript, we discussed the potential implications of PTMs and PQCs in Alzheimer’s disease pathology, based on a comprehensive analysis of their roles within the disease context. We also highlight current gaps in knowledge regarding PTMs and PQCs in AD and outline key areas that require further investigation to advance the field. Additionally, we have included a new section describing a potential integrated therapeutic strategy targeting PTMs and PQC pathways.

2. While the topic is relevant, the manuscript does not offer a clear conceptual advance beyond existing reviews. The sections on PTMs and PQC are mostly presented independently, and their integration into a unified, disease-specific framework remains limited. For example, a mechanistic framework could be introduced describing how early PTMs (e.g., tau phosphorylation or acetylation) selectively disrupt specific PQC components (such as CMA or UPS), thereby driving a stepwise transition from soluble protein states to toxic aggregates and ultimately to global proteostasis failure.

Response: We have discussed that PTM can affect the PQCs in AD. According to the reviewer’s suggestion, we added the text section explaining how PTMs and PQCs affect each other in AD.

3. Several parts of the manuscript, particularly the description of the protein quality control system, are overly general and resemble textbook-style summaries rather than a focused discussion of Alzheimer’s disease. More emphasis should be placed on disease-specific mechanisms, such as neuron-type vulnerability, subcellular compartmentalization, or AD-relevant experimental findings.

Response: A general overview of PQC systems and PTMs is necessary to provide readers with foundational context. Building on this, we discuss the roles of PTMs and PQCs in Alzheimer’s disease and their potential implications in disease pathology. This section has been extensively revised to improve clarity and coherence.

4. In addition, the section on therapeutic implications remains superficial and would benefit from inclusion of more concrete examples, such as specific molecular targets, emerging strategies, or ongoing clinical approaches. For example, the authors could discuss therapeutic strategies targeting tau acetylation (e.g., HDAC inhibitors) or enhancing protein clearance via modulation of autophagy or the ubiquitin–proteasome system, including relevant preclinical or clinical developments.

Response: In the revised manuscript, the therapeutic implications have been updated, and potential targets are described. We also propose and discuss combined strategies to control PTMs and PQCs along with antibody-based therapies to improve outcomes in Alzheimer’s disease progression.

Minor comments 

1. The quality and resolution of Figures 1 and 2 do not appear to be optimal. We recommend that the authors improve the clarity and legibility of the figures.

Response: According to the reviewer’s comment, we have improved the figures 1 and 2.

2. The information in Table 1 is partially repeated in the subsequent text, which reduces readability and disrupts the manuscript's overall flow. The authors are encouraged to avoid redundancy by restructuring this section, for example, by focusing the text on mechanistic insights, critical discussion, or disease-specific aspects rather than reiterating the tabulated content.

Response: In the Table 1, we have summarized the importance of PTMs in AD, which we think will be helpful for the readers. We also added how these PTMs mechanistically influence the AD pathology here in the revised version.

3. In Section 2, the sentence „Collectively, these observations indicate that Aβ is an active component of innate immune defence system the brain” - is grammatically incorrect (missing article and preposition) and should be revised to „Collectively, these observations indicate that Aβ is an active component of the brain's innate immune defense system.”

Response: We have corrected this grammatical error.

4. In Section 3.3, the phrase „modified Aβ species might be poorly handle by PQC systems” contains a grammatical error and should be corrected to „poorly handled”.

Response: We have corrected this grammatical error in the revised manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

This is a very comprehensive and due review which may be published after minor improvements and additions.

There are a lot of reviews dealing with AD and related forms of neurodegeneration in various Journals and books. However, the present paper stands out from similar reviews due to its originality and breadth of coverage. Special attention is paid to the roles of various protein modifications (PTMs) and the protein quality control in the development of AD. The authors convincingly demonstrated that A- beta are not just a by-product of AD and other forms of neuropathology but also play important roles in innate immunity of the organism e.g. due to antimicrobial activity. In the frame of discussion of the role of PTMs the authors paid special attention to the consequences of these processes and their possible therapeutic significance and targeting. The authors described in detail the mechanisms underlying the A-beta cascade including production of amyloid plaques and the details of clearance processes. There are several queries and remarks to the ms.
1. It will be nice if the authors at least mention the role of angiotensin-converting enzyme (ACE2) which interacts with neurotransmitters and plays an important role in neurodegeneration including AD.
2. The authors did mention HSP70 among other hsps but it is necessary to emphasize its pivotal antiinflammatory role in neurodegeneration.
3. Unfortunately, the roles of non-coding RNAs such as mir-200, mir-141 etc in AD pathogenesis were not even mentioned.
4. It will be nice to discuss the role of astrocytes and other brain cells in the AD development (e.g. models of AD due to chronic astrocytic failure).

Author Response

Reviewer 3.

This is a very comprehensive and due review which may be published after minor improvements and additions.

 

There are a lot of reviews dealing with AD and related forms of neurodegeneration in various Journals and books. However, the present paper stands out from similar reviews due to its originality and breadth of coverage. Special attention is paid to the roles of various protein modifications (PTMs) and the protein quality control in the development of AD. The authors convincingly demonstrated that A- beta are not just a by-product of AD and other forms of neuropathology but also play important roles in innate immunity of the organism e.g. due to antimicrobial activity. In the frame of discussion of the role of PTMs the authors paid special attention to the consequences of these processes and their possible therapeutic significance and targeting. The authors described in detail the mechanisms underlying the A-beta cascade including production of amyloid plaques and the details of clearance processes. There are several queries and remarks to the ms.

1. It will be nice if the authors at least mention the role of angiotensin-converting enzyme (ACE2) which interacts with neurotransmitters and plays an important role in neurodegeneration including AD.

Response: The reviewer raised an important point. According to the reviewer’s suggestion, we have discussed the role of ACE 2 in AD in the revised manuscript.

2. The authors did mention HSP70 among other hsps but it is necessary to emphasize its pivotal antiinflammatory role in neurodegeneration.

Response: According to the reviewer’s suggestion, we have discussed the pivotal anti-inflammatory role of HSP70 in neurodegeneration in the revised manuscript.

3. Unfortunately, the roles of non-coding RNAs such as mir-200, mir-141 etc in AD pathogenesis were not even mentioned.

Response: We acknowledge the critical role of non-coding RNA biology in the pathology of Alzheimer’s disease. We also recognize that non-coding RNAs represent promising therapeutic targets that could be integrated with Aβ-lowering approaches, as well as strategies aimed at modulating PTMs, PQCs, and regenerative therapies, to achieve optimal outcomes. However, in this review, we have chosen to focus specifically on PTMs and PQC mechanisms and their roles in AD pathology.

4. It will be nice to discuss the role of astrocytes and other brain cells in the AD development (e.g. models of AD due to chronic astrocytic failure).

Response: We thank the reviewer to raise this point. In the revised manuscript, we have discussed the role of astrocytes and other brain cells in the AD pathology.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors,

In Figure 2, there appears to be a typographical error that should be corrected.

Overall, I believe that after these minor revisions, the manuscript could be suitable for acceptance.

Author Response

Reviewer 2

Dear Authors,

In Figure 2, there appears to be a typographical error that should be corrected.

Overall, I believe that after these minor revisions, the manuscript could be suitable for acceptance.

Response: We thank the reviewer for pointing out the mistake in the Figure 2. We have corrected the typing mistake (Neuro Aggregated Tangles to Neuro Fibrillary Tangles).