Review Reports - Synaptic Plasticity in Neurodegenerative Diseases: Impact of Exercise as Promising Therapeutic Tool

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript reviews the role of exercise-induced modulation of synaptic plasticity in neurodegenerative diseases, a topic of clear biological and clinical relevance. However, despite the extensive citation of the literature, the review does not appear to add substantial new insight to the field. The central mechanisms discussed, including neurotrophin regulation, modulation of neuroinflammation, hormesis, and exercise-related benefits across multiple neurodegenerative disorders, are already well established and have been comprehensively covered in recent reviews. The manuscript remains largely descriptive and does not sufficiently advance current understanding through critical synthesis, conceptual innovation, or disease-specific translational insight. As a result, the overall contribution is incremental rather than novel.

There are certain areas of the text that have been copied from other manuscripts word for word: "Dance is a multifaceted activity that includes physical exercise and cognitive, social, and artistic components, which are linked to visual-spatial, cognitive, and executive functions in individuals"

Even though this manuscript has been cited in an other area, directly copying sentences should be cited in the appropriate area, while using appropriate quote signs.

Comments:

Can the authors clearly articulate what novel conceptual or mechanistic insight this review provides beyond previously published narrative reviews on exercise, synaptic plasticity, and neurodegeneration? If novelty lies in integration rather than discovery, this should be explicitly defined and justified.
The manuscript predominantly summarizes established molecular pathways such as BDNF, IGF-1, VEGF, AMPK/SIRT1/PGC-1α, and NF-κB signaling. Can the authors critically evaluate conflicting findings in the literature, particularly discrepancies between animal and human studies, rather than reiterating consensus mechanisms?
Multiple neurodegenerative diseases are discussed in parallel. Can the authors clarify how shared mechanisms translate into disease-specific differences in synaptic plasticity, responsiveness to exercise, and therapeutic potential, or alternatively justify the breadth of scope chosen?
Clinical trial data are presented descriptively. Can the authors provide a more critical discussion addressing why clinical outcomes are heterogeneous, including factors such as disease stage, exercise modality, intensity, adherence, and outcome measures?
The translational implications remain general. Can the authors propose clearer, evidence-based guidance on how exercise interventions might be realistically individualized and integrated into routine clinical care for specific neurodegenerative conditions?
The conclusions largely restate established concepts. Can the authors more clearly identify unresolved knowledge gaps and define concrete future research directions that emerge specifically from this review?

Author Response

Reviewer 1

Even though this manuscript has been cited in another area, directly copying sentences should be cited in the appropriate area, while using appropriate quote signs.

We thank R1 for the constructive criticism.

First, we apologize for missing inverted commas Dance is a multifaceted activity that includes physical exercise and cognitive, social, and artistic components, which are linked to visual-spatial, cognitive, and executive functions in individuals; the sentence, is reported in inverted commas and followed by a comment in the revised manuscript, page 6, lines 285-288.

Comments:

1. Can the authors clearly articulate what novel conceptual or mechanistic insight this review provides beyond previously published narrative reviews on exercise, synaptic plasticity, and neurodegeneration? If novelty lies in integration rather than discovery, this should be explicitly defined and justified.

R: Thank you for this comment, that helps us to better clarify the aim. The novelty, indeed, lies in discussing as integrated parts the biomolecular mechanisms underlying synaptic plasticity decline/loss as targets of exercise, specifying exercise regimens. To our knowledge, literature covers these topics as separate ones. Furthermore, the reports do not delve into the effectiveness of different exercise regimens, as we did herein in paragraph 3. “Exercise Regimens…”. However, the general features of aerobic/anaerobic/resistance/mind-body exercises give indications on the best possible association exercise-target(s) within a certain disease type, they are not sufficient to design a personalized protocol, as stated in the revised manuscript, page 14, line 596-603.

2. The manuscript predominantly summarizes established molecular pathways such as BDNF, IGF-1, VEGF, AMPK/SIRT1/PGC-1α, and NF-κB signaling. Can the authors critically evaluate conflicting findings in the literature, particularly discrepancies between animal and human studies, rather than reiterating consensus mechanisms?

R: Conflicting findings and discrepancies between data from animal and human studies are better addressed in the revised manuscript, pages 7-8, lines 310-338.

3. Multiple neurodegenerative diseases are discussed in parallel. Can the authors clarify how shared mechanisms translate into disease-specific differences in synaptic plasticity, responsiveness to exercise, and therapeutic potential, or alternatively justify the breadth of scope chosen?

R: Comments on how common mechanisms translate into disease-specific differences and, therefore, the need for personalized treatments are addressed in the revised manuscript, page 14, lines 571-581.

4. Clinical trial data are presented descriptively. Can the authors provide a more critical discussion addressing why clinical outcomes are heterogeneous, including factors such as disease stage, exercise modality, intensity, adherence, and outcome measures?

R: A critical discussion addressing the factors underlying clinical outcome heterogeneity are addressed in the revised manuscript, page 13, lines 534-551.

5. The translational implications remain general. Can the authors propose clearer, evidence-based guidance on how exercise interventions might be realistically individualized and integrated into routine clinical care for specific neurodegenerative conditions?

R: That is the major point. Albeit the undeniable beneficial effects induced by exercising, the indications for exercise-based interventions are neither solid nor well categorized in a guidance document, in part because of specific-disease differences among different neurodegenerative diseases, even if sharing common mechanisms (please see point 3), in part because the discrepancy between data from animal and human studies, that does not allow an immediate species-to-species transfer (please see point 2), but especially, because the indication on exercise as a non-pharmacological therapy to be integrated within the treatment of neurogenerative diseases is still far to be taken in serious consideration. Such an indication should come first from general practitioners, then from specialists and professionals including kinesiologists with specific expertise in exercise “prescription” to ensure appropriate evaluation of training variables, like intensity, volume, frequency and progression.

To this purpose it is mandatory first to better integrate communication among professionals who take care of the patients (i.e., neurologists, neuropsychologists, physiatrists, physiotherapists, kinesiologists) and second, not less important, to find/set dedicated clinical-research centers capable of integrating exercise interventions with systematic biomolecular monitoring (i.e., BDNF, IGF-1, VEGF, inflammatory markers).

Once these issues - still quite completely neglected - are set, it will be possible to translate the personalized treatments into clearer evidence-based guidance, as addressed.

All these issues are discussed in the revised manuscript, page 13, lines 542-549 and pages 13-14, lines 559-584.

6. The conclusions largely restate established concepts. Can the authors more clearly identify unresolved knowledge gaps and define concrete future research directions that emerge specifically from this review?

R: Gaps in knowledge and purposes to define concrete research directions are discussed in the revised manuscript, Conclusion, pages 13-14, lines 559-584 (please see also point 5).

Reviewer 2 Report

Comments and Suggestions for Authors

The review from Farina et al. entitles “Synaptic Plasticity in Neurodegenerative Diseases: Impact of Exercise as Promising Therapeutic Tool” describes the effect of exercise in neurodegenerative diseases. The authors suggest that. The authors suggest that different types of moderate physical activity may have beneficial effects on the development of certain beneficial diseases. The manuscript is well organized and includes interesting results on this topic. I have a few suggestions that could improve the manuscript.

I would like the authors to highlight that exercise modulates brain activity in humans, and its effect can be observed in EEG recordings. Aerobic exercise can induce short-term neuroplasticity in the human cortex. However, this effect does not occur in some neurodegenerative diseases as in Alzheimer's disease. Acute exercise does not modify brain activity and memory performance in a mouse model of Alzheimer's disease (Mike Stein et al. 2017; PLoS ONE 12(5): e0178247). Thus, the Alzheimer's Society has indicated that “Studies looking at the effect of exercise in middle-aged or older adults have reported improvements in thinking and memory, and reduced rates of dementia”.

Although the authors mention IGF-I in the manuscript, they do not indicate that exercise produces an increase in the entry of IGF-I into the brain. For example, physical exercise increases the activity of the hippocampus, favoring memory processes Carro et al 2000; Journal Neuroscience 20: 2926-2933. Later studies have shown the importance of IGF-I in synaptic plasticity.

You write about the effect of exercise on brain activity through the increase in BDNF activity, for example in Section 3.1, aerobic exercise. However, you should be more precise in the description by indicating the areas of the brain where BDNF increases. The same occur in other paragraphs.

Author Response

Reviewer 2

Thanks to Reviewer 2 for your appreciation of our paper and for the useful advice to ameliorate it.

R: A topic on EEG monitoring to investigate brain activity modulation in humans is addressed in the revised manuscript, page 8, lines 331-338; related references are quoted.

R: Topics on IGF-I are present in the revised manuscript, page 8, lines 316-321, and related references are quoted.

R: In rat model of vascular dementia BDNF expression rises after treadmill exercise in the hippocampal dentate gyrus, as stated in the manuscript, page 4, line 178; in mice, aerobic exercise increases BDNF protein and gene expression in the hippocampus, page 4, lines 182-183.

In general, beside hippocampus, the brain areas expressing increased BDNF after aerobic exercise are areas involved in learning, memory, mood, and motor control, like prefrontal cortex, motor cortex, striatum, cerebellum, as stated in the revised manuscript, page 4-5, lines 185-188. However, studies detecting neurotrophins’ upregulation in brain areas are almost from animals, since in humans the rise is detected in blood, as stated in the revised manuscript, page 7, lines 310-315.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have addressed the comments adequately.