Success in reversing dementia in mice sets the stage for human clinical trials | Hacker News Reader

Success in reversing dementia in mice sets the stage for human clinical trials

tohoku.ac.jp

99 pointsgmays21 comments

Questions.

> "We discovered the novel, disease-modifying therapeutic candidate SAK3, which, in our studies, rescued neurons in most protein-misfolding, neurodegenerative diseases."

Grepping for Creutzfeldt Jakob Disease (cjd) and prion yielded nothing. And yet we also have research [1] [2] claiming a function for beta amyloid, implying that the protein's folding is a favorable outcome.

For those more well informed than me on these topics, could this mechanism present value against prion-driven misfolding? And is there a rift in consensus over whether beta amyloid is a misfolded protein? I recognize that both of these cases are very, very different in that prions perpetuate the misfolding whereas beta amyloid isn't known to do so.

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505565/

[2] https://www.scientificamerican.com/article/harder-evidence-b...

CJD is extremely rare in humans, so it's easy to understand why AD and LBD would be priorities. But CJD does manifest endogenously in sheep, so they could give it a go in vitro and in vivo. That might be more informative than the mouse disease models, which are not true analogs of the human disease forms.

It’s extremely rare because we take extreme measures to make sure it stays rare. When you dress out your deer or squirrel, make sure to follow current recommendations.

Has anyone ever taught a cat to properly dress a squirrel?

Think I'm going to have to move back to disposable utensils when feeding them....

Cats don’t seem to go after the nerve tissues on animals they kill.

But, they have other diseases, so we’re careful to keep the cat dish separate from the rest of the dishes.

The only bits my cats leave are pieces of the digestive tract - I don't know the first thing about anatomy but it looks like kidneys and intestines. They've only caught a few things big enough that they can't eat it in one sitting (or they try anyway and throw it all back up)

"Fortunately" squirrel screams are the worst so I can usually rescue them before the meal begins. Literally just happened 20 minutes ago...

I was just watching “Reversing Dementia with diet, 2021 update - dr Paul Mason”[1] he makes the quite convincing case that it’s a metabolic disorder not a genetic one, that incidence is increasing due to western diet and lifestyle (as with so many things), and that particularly fructose, and oxidised unsaturated fats and seed oils are implicated in the formation of amyloid plaque, in insulin resistance and therefore starvation of brain tissue, in damage to the blood brain barrier.

And that reducing these things can reduce the chance of developing these diseases, that ketones from a ketogenic diet can bypass insulin resistance and provide brain fuel which improves symptoms in people who have these diseases, and that apoE is about cleaning up plaques and variant 4 most associated with Alzheimers is the most easily damaged one and therefore less effective at cleanup in metabolically unhealthy people - but less necessary in metabolically healthy people who aren’t creating as many tangles to clear up.

It is not the first time I’ve seen claims along these lines - dementia as type 3 diabetes, brain function in elderly people improved with diet changes, etc. If insulin resistance of the blood brain barrier in middle age causes brain cells to starve to death, and that’s what causes the brain dysfunction and symptoms it doesn’t bode well for ever finding a “cure” anymore than there could be a drug cure for a missing limb.

[1] https://www.youtube.com/watch?v=muAvJ1y64PA

Why do you think that dementia is just one thing caused by diet?

Why can't it be many things, some of which are metabolic related?

I don’t think that.

It is possible that fasting or good diet slows down natural aging a bit, perhaps even quite a bit.

This is still far from settled science, not least because we struggle to understand what aging really is and we have hard time measuring it. The only available methods that measure aging of tissues (methylation clocks) have unclear causality (e.g. when a tissue becomes "younger" after some intervention, is it really younger or is the clock just out of sync now?)

But if aging manifests as dysregulation and good food/fasting can fix that dysregulation a little, one would expect that the diseases of aging could either slow down or even reverse a little.

That won't work indefinitely, though. Not even veteran fasters live to be 150. In order to get rid of the curse of dementia, we need to fight aging itself. Much like we did away with cholera through introduction of good hygiene practices, not just through better symptomatic treatment.

My mother suffers from dementia and I would sign her up in a heartbeat. Worst case is it kills her, and her suffering is over. Best case it cures her and her suffering is over.

Dementia is the cruelest disease, more so than others like cancer.

Worst case may be an unforeseen condition or outcome where she's alive but worse-off than before or without.

But I agree. In the same position, I would do the same.

Given what I saw in my grandmother when she became ill with dementia, I don't see a much worst case. Maybe if she had survived for longer in an even slower decline... but heart meds already gave us that.

The same group also published this paper on SAK# with Alzheimer's Disease in 2019

https://pubmed.ncbi.nlm.nih.gov/3060144/

key point: in mice

> key point: in mice

Yes. Mice don't get endogenous Lewy Body disease. The mouse model in the study is derived by injecting α-Syn preformed fibrils into the striatum. Whether SAK3 application will translate into human LBD treatments might depend on other aspects of the human disease process. With that understanding, the next step is to give it a go in human trials.

I'm sure they'll have no shortage of volunteers. It's the only game in town, and LBD patients have nothing to lose.

yep, hopefully something good comes out of it

A library[1] small molecule drug that reverses dementia by acting on a calcium channel based on mouse data?

Press X to Doubt

[1] https://www.tocris.com/products/sak-3_6239

Doubt is healthy and free but it doesn't get you anywhere.

If you evaluate the mechanism they explain, your prognosis will be better informed. Really the size of the molecule is neither here nor there. It's the therapeutic application that counts.

> SAK3 enhanced the proteasome activity via CaMKII activation

Consider why that might be effective.

It is explained clearly in their AD paper abstract.

https://pubmed.ncbi.nlm.nih.gov/3060144/

> Thanks to advances in medical technology, Robert Gu is slowly recovering from Alzheimer's disease. As his faculties return, Robert (who has always been technophobic) must adapt to a different world, where almost every object is networked and mediated-reality technology is commonplace. Robert, formerly a world-renowned poet but with a notoriously mean-spirited personality, must also learn how to change and how to rebuild relationships with his estranged family. At the same time, Robert and his granddaughter Miri are drawn into a complex plot involving a traitorous intelligence officer, an intellect of frightening (and possibly superhuman) competence hiding behind an avatar of an anthropomorphic rabbit, and ominous new mind control technology with profound implications.

[0]: https://en.wikipedia.org/wiki/Rainbows_End

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