Understanding the Liver’s Role in the Clearance of Aβ40

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The paper presents some interesting data however makes too bold claims such as ”suggests it (liver) would not be an effective target for the treatment of Alzheimer’s disease” based on limited data. 

 

 

1. The paper makes bold statements without enough evidence. In discussion (starting 309), “Our western blots of livers exposed to unlabeled Aβ40 did not show any uptake. The timeframe for our experiment was 30 seconds, in contrast to the previous study’s significantly longer 90-minute endpoint. However, our shorter timepoint would still be likely to show a significant level of uptake if the liver were rapidly clearing Aβ40 resulting in its half-life of 1.5 to 3 minutes in plasma as previously reported.” This statement is made with no evidence. Plasma and cell culture are very different models. How can the authors be sure they can detect low levels of AB? They report no detection limit on there Western blots. They use very high levels of AB in the Western blots but do not show loading of low AB levels. More details experiments exploring detection limits, and time course are needed before such statements can be made. Also spiking experiments to liver to demonstrate effective recovery and detection would be helpful.
2. Figure legends frequently lack details on number of experiments and/or number of animals.
3. The 3H-Aβ40 experiments are perhaps the most interesting but very limited. The localization of most AB is not known. In addition without proper pharmokinetic experiments too much speculation should not be drawn.
4. Single-pass experiments, although interestedly, cannot be used to suggest that liver is not an effective target of Alzheimer’s disease. As the authors acknowledge “There is also the possibility that binding of Aβ40 by other molecules in the peripheral circulation may be necessary for its liver uptake.” More experiments besides single-pass experiments should be considered if such strong conclusions are proposed.

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

In this study, X et al. investigate the possibility of using the clearance of peripheral beta-amyloid (Aβ) as a target for the treatment of Alzheimer’s disease (AD). Specifically, previous reports indicate that the liver uptakes a large amount of peripheral Aβ. Consequently, the liver uptake and clearance of Aβ could strongly impact the brain levels of Aβ and, in turn, influence disease progression.

Another crucial point rightfully stressed by the authors is that the fenestrated endothelium of the liver capillary (sinusoids) plays a crucial role in regulating the passage of different molecules from the bloodstream to the hepatocyte. As a consequence of these considerations, the authors suggest that the progressive reduction of sinusoidal fenestrations associated with aging could correlate with reduced liver clearing of Aβ.

To study this hypothesis, they used different approaches to compare the hepatic uptake of Aβ in young and adult rats. In contrast to previous studies, they did not find significant accumulation of Aβ in the liver in both young and old rats. However, the data suggest that the analysis of peripheral Aβ dynamics is much more complex than expected and could be strongly influenced by the experimental procedures employed to measure liver uptake. Overall, this is an interesting report clarifying important methodological aspects that should be considered when studying peripheral Aβ kinetics.

Before publication, some minor points should be addressed:

The reduction in both the number and size of sinusoidal fenestrations is a well-described condition in aged rats. However, the authors should quantify sinusoidal porosity (a parameter well known to the authors) before concluding that there is no difference.

In its present form, the introduction communicates that the reduced number of fenestrations is a condition mainly linked to aging. This is not the case, as reduced porosity is common to pathological conditions including toxic (PMID: 17187425) stress and fibrosis (PMID: 26188075 ), with a profound impact on major biological processes.

Author Response

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Author Response File: Author Response.pdf