Highest Rated Comments


BeautyIsDumb30 karma

I must say that I'm a huge fan of your work. SUS is probably the coolest development in neuroscience in the last 15 years. I’ve been waiting for the opportunity to ask you these questions for a long time now. Hopefully you can answer them:

1) How do you expect SUS coupled with microbubbles therapy to translate into humans? How do you plan to overcome differences in skull thickness and overall head size?

2) In your paper titled "Scanning ultrasound removes amyloid-beta and restores memory in an Alzheimer's disease mouse model", you find that microglia is activated by SUS. How can you see a 5-fold increase in the area of CD68 immunoreactivity without alteration in the size of microglia cell bodies?

3) In all your studies (that my university's library grants me access to read), you employ microbubbles without SUS as control, but not SUS without microbubbles. Why not test the effects of SUS on its own?

4) What's the point of focused ultrasound beam if you're going to move it in 1.5 mm increments to cover the entire forebrain? Why not use a more diffuse beam and then move it in larger increments?

5) If you hypothesize that SUS coupled with microbubbles works by opening the BBB, why do you need to sonicate the entire forebrain with SUS and not just the areas adjacent to the BBB?

6) When I was reading your papers, I was visualizing a plumber who was using a big vibrator to shake a partial blockage through a pipe as water is flowing through it, and using the content inside the pipe to remove the soft sticky goo that's blocking the pipe. Is it possible that SUS coupled with microbubbles doesn't actually work by opening the BBB, but rather, that it works by using those non-sticky microbubbles as the content inside the pipes that's vibrating and causes amyloid plaques to lose their grip on blood vessels? If my hypothesis is correct, you would find a milder (but still significant) reduction in amyloid plaques with SUS without microbubbles, and you would also find a reduction in amyloid plaques if you had sonicated the entire forebrain with SUS after microbubbles injection, but prevented the vibration within the BBB. Basically, what I'm saying is that opening the BBB isn't a requirement for SUS coupled with microbubbles to work, it's just a nice bonus.

7) Are you looking for new research assistants or graduate students? Asking for a friend ;)

BeautyIsDumb7 karma

Microglia are actually excellent at digesting beta amyloid, they've been doing it since you were a fetus. It's only when you age that microglial clearance of beta amyloid starts to diminish, which is believed to be one of the factors leading to the development of AD.

You could 'boost' microglial degradation of beta amyloid by proinflammatory endogenous cytokines, which is probably one of the reasons Dr. Gotz believes that opening the BBB is going to improve clearance of beta amyloid. Once microglia are activated, they are capable of performing macrophage-like immune functions, like cytokine release and phagocytosis. The advantage of opening the BBB is that you allow for more access for immune mediators that may activate microglia, compensating for its reduced activity in AD. By opening the BBB, you're also allowing perivascular macrophages (line walls of cerebrall blood vessels in the BBB) to create a 'peripheral sink' for beta amyloid, allowing it to pass out of the BBB and into the periphery, where peripheral macrophages may easily degrade it.

I've intentionally avoided asking Dr. Gotz how he thinks SUS activates microglia, because we're very far away from understanding this process. However, what is clear is that microglia is entirely capable of degrading beta amyloid, because it's done it your entire life. What causes microglia to 'slack off' when we age? We don't know. What's unique about Dr. Gotz's research is that he's able to show that he can turn 'coach potato microglia' back into 'resilient microglia'.