. Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer's disease mouse model. Sci Transl Med. 2015 Mar 11;7(278):278ra33. PubMed.

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  1. This is an interesting and provocative study. There have been several related studies that have generated some interest, but this work has been at the margins of most people’s expertise and the technical aspects of the ultrasound treatment are hard for a novice to evaluate.

    However, the present study reports the ability to open the BBB over a broad area of cortex. It is not clear how long the treatment opens the barrier and this is a critical piece of information. The analysis of tissue damage that accompanied the ultrasound treatment is superficial and requires a more detailed examination.

    The Y maze data suggests that ultrasound improves behavior in APP23 mice; however, it is not evident that they have a transgene effect in their APP23 transgenic mice, complicating the interpretation of these data. The novel object-recognition data appear sound. In summary, the behavioral data hold promise.

    The plaque reduction with five treatments over six weeks is about 50 percent and these data are impressive. The Aβ peptide analysis is a bit unusual and it is not obvious why soluble Aβ levels would fall, although the effect sizes are substantial.

    The most controversial aspect of this study revolves around microglial “activation.” “Activation,” a nebulous term, is not necessarily correlated with morphology and is a poor metric. For this analysis the plaque-associated macrophages/microglia need to be examined in greater detail (the movie wasn't available). The low power images are not very informative, but the CD68 and NFkB analysis is helpful. There appears to be a difference in Iba1 staining within an hour of ultrasound treatment, suggesting that the treatment elicits very rapid changes in microglia. One wonders if this is reflective of their initiation of phagocytosis. It is difficult to know what to conclude from the skeletonized microglia analysis, but I don't believe it can necessarily be interpreted as “activation.”

    The argument that albumin is involved in amyloid clearance in vivo is not convincing. When the BBB opens, all serum proteins enter the brain.  Many of these, most prominently complement, could support the phagocytic clearance of Aβ.

    In summary, the basic phenomenology is compelling and bears further study.

  2. This is a very innovative and interesting paper. Naturally, I would have expected that such a treatment would make the mice worse and not better. As the authors acknowledge, more work appears necessary to follow up on this provocative and novel finding.

  3. We are currently doing experiments to address some of the issues that have been raised by Dr. Landreth. There is a wealth of data established in species ranging from rodents to macaques, showing that ultrasound allows for a safe opening of the BBB (some of this work has been cited—see e.g., papers by the Hynynen and Konofagou groups cited above). With the parameters chosen by us, the BBB opens transiently and selectively for a few hours and closes within one to two days. Regarding the behavioral data, the first cohort of mice was analyzed in the Y-maze. To strengthen our behavioral analysis, we conducted not only a novel object recognition test (referred to by Dr. Landreth) but also an active place-avoidance test. Regarding albumin, this serum protein is indeed only one of many factors entering the brain. Some of these have been shown to interact with Aβ, including albumin, transthyretin, and immune factors, but we chose to look at albumin first as it is the most abundant plasma protein, it is reduced in AD brains, and we were detecting its entry into the brain with Evans Blue in the ultrasound-treated mice. We are, at this stage, not claiming that albumin is the key protein in this process, we only show in vitro that albumin facilitates the uptake of amyloid, suggesting that it could play a role in vivo. The skeleton analysis complements the intensive microglial analysis and additional supporting data are shown in the supplementary movie file. We do show that amyloid is taken up by microglia into their lysosomes and our data on “cleared plaques” show that scanning ultrasound activates microglia to clear amyloid.

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