Autophagy Markers Are Altered in Alzheimer’s Disease, Dementia with Lewy Bodies and Frontotemporal Dementia

Round 1

Reviewer 1 Report

The submitted manuscript presents the findings of a study that analyzed and compared ATG5, UBQLN2, ULK1, and LC3 concentrations in 66 brain specimens and 120 plasma samples obtained from patients with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and control subjects (CTRL). The obtained results are interesting as they demonstrate alterations in different steps related to the ATG5, UBQLN2, and LC3 autophagy pathways and suggest their potential involvement in the pathogenesis of neurodegeneration. The submitted manuscript is well-written and is free of obvious stylistic, grammatical, or linguistic errors, and exhibits a logical structure. The study was well-designed, and the rationale behind it is effectively explained in the Introduction. The methods employed in the study and the obtained results are sufficiently described and discussed in-depth. However, the study has some limitations and shortcomings that need to be addressed and discussed in more detail in the manuscript:

1.) The major limitation of the study is the significant differences in mean age between the study groups, especially the lower mean age of controls compared to FTD, DLB, and AD groups. Consequently, it raises the question of whether the observed differences in the levels of the studied autophagy proteins could, at least in part, be age-related rather than solely associated with the pathological process itself. Is there knowledge about alterations in ATG5, UBQLN2, ULK1, or LC3 expression/levels, or autophagy in general, during healthy aging? This issue should be discussed in detail within the manuscript.

2.) Interestingly, in the frontal cortex, LC3 levels were increased in DLB and FTD groups compared to AD group, while the opposite was true in the temporal and occipital cortex. Is there any explanation for this?

3.) The following sentence in the Materials and Methods is not well formulated: 'Chi-square test was used to assess the association between gender, as a categorical variable, of subjects with the four groups.' It would be more appropriate to state that the chi-square test was used to analyze differences in gender distribution among the study groups.

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

In this study, the authors reported the alterations of ATG5, UBQLN2, ULK1, and LC3 levels in patients: ATG5 and UBQLN2 levels were decreased in both brain specimens and plasma samples of patients compared to CTRL, while LC3 levels were increased in the frontal cortex of DLB and FTD patients.  This study is potentially interesting, however, some points should be addressed as below:

Points

1. What caused the results of decreased levels of ATG5 and UBQLN2 in the patient's brain and plasma specimens compared to CTRL, while increased levels of LC3 in the frontal cortex in patients with DLB and FTD? It should be discussed in more detail in the discussion section.

2. The relationship between the alterations in ATG5, UBQLN2, ULK1, and LC3 brain specimens and plasma of patientsshould be fundamentally described based on the previous papers published to date in terms of autophagy and neurodegenerative disease pathogenesis.

English should be revised by professional native speaker.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf