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Strengths

- The study addresses an important question: whether the Neu1–PCCA axis regulates APP sialylation, secretase activity, and lysosomal exocytosis, thereby modulating amyloid pathology.

- The framework is novel and supported by a range of evidence (human brain samples, 5xFAD transgenic models, AAV-mediated interventions).

- The authors make a commendable effort to consider sex differences, report negative results, and outline limitations and clinical significance.

- The work contributes a valuable dataset for the field, even if some findings are more correlative than causal.

Major Concerns

- Figure 1a shows NEU1 protein levels in AD brains are not significantly reduced (p = 0.145), contradicting the stated model. Later conclusions about “NEU1 downregulation” appear overstated.

- Evidence is associative mainly, not causal. Missing experiments include site-directed mutagenesis of glycosylation sites, targeted glycoproteomics, and the characterization of catalytically inactive mutants in an in vitro model.

- No behavioral or electrophysiological assays are presented, leaving the translational impact speculative.

- Statistical issues: unclear multiple testing correction, small sample sizes, unbalanced groups, discretized age bins, and lack of genotype × sex interaction models. Some figures/text sections claim significance where p-values exceed thresholds.

Figure and Data Presentation

- Staining figures (e.g., Fig. 1c) are not visually striking and lack quantification. Representative images and quantification would improve clarity.

- Violin plots dominate the paper. Suggestions: add a schematic overview, provide simplified pathway models, include summary trend figures, and improve color palettes for each figure.

- Sialylation assays (SNA binding) are indirect and prone to nonspecific binding; possible validation, such as LC–MS/MS, is needed.

- Western blots are described, but no representative blots are shown, making it challenging to assess robustness.

- Figure legends often lack clarity about statistical tests. Example: Fig. 3d involves repeated measures, but the analysis assumed independence. Mixed-effects modeling would be more appropriate.

Broader Narrative and Interpretation

- The writing style reads like many observations with few insights. The narrative often restates figure data without an integrative interpretation.

- Some conclusions are overstated relative to the data (e.g., sex differences, NEU1 levels). Authors should align claims more closely with statistical support.

- The discussion could better propose specific therapeutic directions based on Neu1–PPCA, acknowledging past failures of amyloid-targeting strategies.

- Questions remain about whether sex-specific effects will generalize to humans and how this might affect therapy design.

Overall Impression

- This is a valuable but incomplete contribution. The Neu1–PPCA axis is a promising mechanistic link between lysosomal dysfunction and amyloid pathology.

- The manuscript would be strengthened by more transparent statistical reporting, causal glycobiology experiments, representative blots, sialylation validation assays in cultured cells, cautious interpretation of sex differences, and a more integrative narrative.

Competing interests

The authors declare that they have no competing interests.

Use of Artificial Intelligence (AI)

The authors declare that they used generative AI to come up with new ideas for their review.