Better drainage of brain debris improves Alzheimer's disease therapies

We're still struggling to accurately simulate a C. elegans. We're a little way off simulating 50+ kg of conscious organism.

Not to mention the ethical implications. If we're happy to run "cradle to the grave" tests on a human simulated to that level of accuracy, why not just run them on actual humans bred for research? We can do that right now, far cheaper.

...of course, maybe that just means that we're the disease model...

Decades at least, we don't even have close to a complete list of the proteins in our bodies which would be needed to start thinking avout simulating them.

500+ years? Last I looked into what some major players in computational neuroscience were doing simulating highly accurate neurons they were doing on the order of maybe thousands of neurons. It’s been a few years so maybe they can simulate 100k today. The human brain has 100billion neurons. And that’s just part of a system. I don’t know how many other cells you’d need to simulate to model just the space between your ears. And I don’t think we’re even talking at the protein level yet of simulations. Proteins are notoriously difficult to simulate. If bitcoin had managed to use protein folding as it’s proof of work I’m not sure we’d even be able to fill the current demand for research let alone simulating an entire human. I don’t think I can fathom the amount of compute we’re talking about to simulate a human at the drug interaction level to any real degree of accuracy.

If you are willing to bend some ethics, brain organoids and other similar organ-on-chip solutions are quite promising. Though it is important to note that scaled down brains may not necessarily express the same behavior vis-a-vis a full sized human cortex.

we can’t simulate a single protein long enough to determine how it folds, even with a supercomputer. we’re so many orders of magnitude away from such a thing it’s basically unthinkable.

Very, very far. There are 10^27 atoms in a human body. Even if you go down to individual proteins, that saves you maybe 4-5 orders of magnitude. That's about a zettabyte of data just to describe initial conditions.

It's that transgenic beta-amyloid mice are not humans with Alzheimer's.

BUT!

As another neuro PhD: this is still an important finding for our understanding of protein (dis)aggregation in the brain. The opposite finding was totally possible. The protein disaggregation could have been independent of CSF flow. The typical HN hot-take is "not so fast, this translational research actually underdelivers," but I prefer, "this fundamental neurosci research has the added bonus of being preformed on a clinically relevant model."

I'm not a doctor. I haven't worked in a wet lab. All this is from second hand conversations and anecdotes.

Mice aren't human.

There's lots of ways to cure cancer in mice. it's practically a joke. Mice can tell you a bit about danger - if your treatment kills the mouse, think pretty hard about that treatment on a human. It might kill the human too, but maybe not. Might be ok for the mouse but not the human, like maybe thalidomide.

The impression I get is, if it's ok for mice it _might_ be ok for humans, so it helps avoid a large swath of super dangerous stuff. But doesn't tell you a whole lot about what happens in humans. I'm sure there are things that kill mice that are effective treatments for humans, but both of those edges are outlier-ish. If it kills the mouse it's probably not worth continuing without a good understanding of why it might work in humans.

It could be that amyloid is the smoke. It could also be residue from the body's fire extinguishers. That is, something breaks, and amyloid accumulation is a consequence of whatever the body does to try to fix it. Maybe it makes it worse. The point is, we don't know, and 30 years of presuming that we do has led us to a giant dead end.

I have the same experience. I got four hours last night, but I worked out this morning. I feel almost normal.

Lymph is fascinating. It is your other circulatory system.

Capillaries are are so narrow they can only allow a single erythrocyte through at the same time. The pressure from your heart causes fluid leakage from the thin vessels. Lymph ducts/nodes help get this fluid back into your blood. Since the heart doesn't pump lymph, that helps move it through your body is actually your musculoskeletal system. That is to a certain degree true from your venous / return flow in your "normal" circulatory system, too. It's why your feet can swell if you're sitting down too much. I'd speculate that lymphatic flow efficiency has local and systemic elements that contribute to it (and so your leg muscles moving lymph help your overall lymphatic system health).

I'm not sure anyone knows the answer to that in specific. In my experience, exercise is often followed by a nap and my inference is that clearing lymph from other tissues somehow encourages the body to also clear lymph from the brain, but I haven't actually found an explanation for how that works.

You might find this general overview of the body's lymphatic system interesting:

https://news.ycombinator.com/item?id=25427090

As noted by the article, it was only recently discovered that the central nervous system had lymphatic drainage (see [1]). I’m simply connecting the results of this mouse study with what we know about the lymphatic system, skeletal muscle, and the apparent benefit of exercise on Alzheimer’s disease risk, to form a hypothesis. I strongly suspect it’s true, but I cannot represent it as fact.

Edit: Here is a more direct answer to your question:

1) Increased localized pressure from contracting muscle pushes lymph away through a vessel.

2) Reduced localized pressure from relaxing muscle allows new lymph to refill the evacuated vessel portion.

3) Lymphatic vessels have valves that keep all this flow moving in the same direction.

4) Given that the lymphatic system is connected to the central nervous system, increased muscular contraction could increase drainage of the brain.

[1] https://www.nature.com/articles/nature14432

It is pretty common to jump into a cold bath after spending time in a sauna

Regardless of actual health effects, it feels fantastic!

I’ve been wondering the same. I think of inducing heat/cold similar to turning a rusty spigot. The first few turns are difficult but the more you do it the easier it gets.

But do spigots in other parts of your body get turned that are also rusty, so to speak?

I notice cold/hot showers help my body regulate my temperature better, generally.

You may also need to buy that mouse from a specific lab for the therapies to have reproducible effects. [1]

[1] - https://www.youtube.com/watch?v=ve4q-1D_Ajo

Rolling sounds good for proprioception. My toddler enjoys being rolled around, and I remember rolling as a kid, and having to adjust to keep going in a straight line. Thanks, I’ll do it again.

Also thanks to this thread for the nudge back into morning exercise. “The Five Tibetan Rites”[0] is a dynamic set that can be committed to memory easy enough, as one example. Jogging around the field with an aging-but-still-faster dog for the morning perimeter check/mark also helps.

[0] https://www.wikipedia.org/wiki/Five_Tibetan_Rites