Sialic Acid Ameliorates Cognitive Deficits by Reducing Amyloid Deposition, Nerve Fiber Production, and Neuronal Apoptosis in a Mice Model of Alzheimer’s Disease

Round 1

Reviewer 1 Report

Review of a manuscript “Sialic Acid Ameliorates Cognitive Deficits by Reducing Amyloid Deposition, Nerve Fiber Production, and Neuronal Apoptosis in a Mice Model of Alzheimer's Disease” by Min Xiao and coauthors submitted to Neurosci, MDPI.

Alzheimer’s disease is a most prevalent neurodegenerative disorder associated with cognitive difficulties, decreased language ability, reduced learning and memory. This disease causes countless sufferings and harm to the patients, and brings a substantial burden to the family and society. There is no efficient medication reverting the course of the disease and no reliable biomarkers to reveal early steps of the disorder.  The authors studied the effects of sialic acid-rich mixed feeds on learning and memory abilities, Aβ formation and hyperphosphorylation of Tau using PS1/APP double transgenic mice model. The topic of their manuscript is an important biomedical problem, the manuscript contains new data which will be important for the readers of Neurosci.

The following corrections should be made.

Abstract

Lines 17-19: “The 2×Tg-AD mice were randomly divided into four groups: AD control group, 17 mg/kg SA-treated AD group, 84 mg/kg SA-treated AD group, and 420 mg/kg SA-treated AD group, then fed to 7 months of age for the behavioral test and 9 months of age for pathological factors investigation”. The sentence is too long and hard to read. It should be divided in two as follows: “The 2×Tg-AD mice were randomly divided into four groups: AD control group, 17 mg/kg SA-treated AD group, 84 mg/kg SA-treated AD group, and 420 mg/kg SA-treated AD group. Mice from all four groups were fed for 7 months of age for the behavioral test and for 9 months of age for pathological factors investigation.”

Introduction

Line 39 “As a transmitter of gangliosides and a part of the brain…” This is a clumsy sentence which should be corrected as follows: ” As a transmitter of gangliosides and one of the chemical component of the brain…”

Line 59:”…and under temperature of 22 ± 2 °C with free access to food and water.” Should be corrected as follows :”… and at  temperature of 22 ± 2 °C with free access to food and water.

Methods

Line 101: “Blood samples were obtained by removing the eyeballs of the mice, and then left to stand for 3-4 hours…” It is unclear what for the blood samples were left to stand for 3-4 hours and at what temperature”.

Results

Figures: The authors should add scale bars for figures 3-5.

Discussion

Line 311: “Aβ is caused by continuous shearing of APP protein by β- amylase and γ-secretase” The sense of this sentence is unclear. It should be rewritten to become understandable.  

Line 333: “It is well known that obesity, hypertension, cardiovascular and cerebrovascular diseases increase the risk of AD [36-38].

The authors should correct this sentence as follows and add a reference: “It is well known that obesity, hypertension, diabetes, cardiovascular and cerebrovascular diseases increase the risk of AD [36-38] + reference “Caveolin: A New Link Between Diabetes and AD. Cell Mol Neurobiol. 2020; 40(7):1059-1066. doi: 10.1007/s10571-020-00796-4:

General comment: The authors should always use abbreviated form of Alzheimer’s disease as AD throughout the whole manuscript. Sometimes, they forget to do it, for example on line 373 and in other places.  

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

Alzheimer’s disease (AD) is the most common degenerative disease of the brain. The clinical features are cognitive impairment, memory loss, dysnomia, and visuospatial disorientation and personality changes.

The main pathological findings in AD are the senile plaques resulted from amyloid β-peptide deposition and nerve fiber tangles created by aggregation of hyperphosphorylated tau protein.

There is an increasing societal cost due to AD. Current treatment of AD use acetylcholinesterase inhibitors and N-methyl-D aspartate (NMDA) glutaminergic antagonists.

Efforts are made to find new molecules in AD treatment armamentarium, with greater impact on disease evolution.

The authors propose sialic acid (SA) (N-acetylneuraminic acid) – a natural carbohydrate involved in brain development could be in the future a new mean to treat AD, based on preclinical studies on transgenic model AD mice.

The mice were divided in 4 groups – with no sialic acid diet, with low, medium, and high sialic acid diet. Also

The authors tested spatial memory and learning of the mice using Morris water maze and anxiety of mice using open field test. The results were better in the groups with sialic acid diet.

There was a reduced number of amyloid plaques and nerve fiber tangles in mice with sialic acid diet, indicating that SA could reduce the neuronal injury in AD mice. Also, SA could reduce blood lipids, with a potential effect on vascular disease co-existing with AD. 

The main question of the study is the impact of sialic acid diet on mice model of AD. The authors demonstrate a positive impact on pathological hallmarks of AD in the mice with  sialic acid diet, compared with AD mice without dialic acid diet.

It is an interesting approach to find new molecules for AD treatment.

It is an orginal research focused on AD model. Sialic acids have involvement in immunology and tumor biology, as well as in hereditary diseases,

The papaer is well written, easy to read.

The conclusions are in according to the results of the study. The results confirm the  ipothesis of the role of sialic acid in amelioratimg AD.

I think the autors should give the definition of  B6C3F1 WT MICE. 

Author Response

Point 1: I think the authors should give the definition of B6C3F1 WT MICE.

Response 1: “WT” means wild type. “B6C3F1” is the strain code of mice and is the offspring of female C57BL/6 (also known as C57 Black 6 or B6) and male C3H (C3), so the resulting F1 offspring called “B6C3F1”. B6C3F1 mice is one the most widely used inbred strain for knockout and transgenic models.