Tau PET imaging beats amyloid-based approach in battle against Alzheimer’s | Hacker News Reader

Tau PET imaging beats amyloid-based approach in battle against Alzheimer’s

healthimaging.com

71 pointshoward94115 comments

A prediction: the generic, low-cost drug dasatinib, a senolytic that selectively destroys senescent cells and can pass the blood-brain barrier, will be the best Alzheimer's treatment of the next decade, starting just as soon as the Mayo Clinic gets around to running a trial for that rather than focusing on fibrotic disease.

https://doi.org/10.1111/acel.12840

"Tau transgenic mice with late stage pathology were treated with senolytics to remove senescent cells. Despite the advanced age and disease progression, MRI brain imaging and histopathological analyses indicated a reduction in total NFT density, neuron loss, and ventricular enlargement. Collectively, these findings indicate a strong association between the presence of NFTs and cellular senescence in the brain, which contributes to neurodegeneration."

https://doi.org/10.1038/s41586-018-0543-y

"Here we show a causal link between the accumulation of senescent cells and cognition-associated neuronal loss. We found that the a mouse model of tau-dependent neurodegenerative disease accumulates p16INK4A-positive senescent astrocytes and microglia. Clearance of these cells as they arise using INK-ATTAC transgenic mice prevents gliosis, hyperphosphorylation of both soluble and insoluble tau leading to neurofibrillary tangle deposition, and degeneration of cortical and hippocampal neurons, thus preserving cognitive function. Pharmacological intervention with a first-generation senolytic modulates tau aggregation."

Haven’t lots of drugs shown promise in mice, but then failed in humans? Why is this one different?

Was cognitive performance improved, though?

Still no closer to a cause.

Recent successes with antivirals, and high correlation with bacterial infection, should be getting the bulk of funding, but they are mostly still puttering with plaques and tangles.

What will all the protein folding specialists do when it turns out to be a virus or something?

That’s because research is incredibly underfunded:

https://www.aarp.org/health/brain-health/info-2015/alzheimer...

https://www.alzheimers.net/2013-09-25/alzheimers-research-fu...

A much larger amount of money has been put in HIV research over the past 25 years, for example, and great progress has been made.

Imagine an equal amount of funding for Alzheimer's over the past 25 years.

That makes it the much more urgent not to squander it all on hypotheses that failed 20 years ago.

Sure, they can move the small amount of funding to some other promising idea for a decade until it sputters, then pick the next promising idea.

Considering the cost to society, we really need invest a lot more now. Then we can look at several ideas in parallel, etc

Increased funding tends to depend on success with what is being spent. Spending more over the past two decades would have been throwing good money after bad, so it is good it wasn't spent. Stewards of that spending have demonstrated their foolishness, year in and year out.

The difficulty now is how to wrench control of such spending out of the hands of those who squandered it. Probably the American and maybe European agencies will find themselves unable, being fully captured.

Spot on. The immune system is a classifier. So it makes sense autoimmunity, in general, is a classification problem (triggered by infections or commensal dysbiosis).

Occam's razor favors this simpler hypothesis, and there's some convincing evidence out there in top journals. See introduction in this recent preprint: https://www.biorxiv.org/content/10.1101/2019.12.18.881433v1 and other references in this thread https://news.ycombinator.com/item?id=21917884.

To elaborate a bit further on the first paper, our own commensal bacteria mimic important proteins to avoid being recognized as invaders by the immune system. The immune system has probably evolved to use this commensal mimicry to update its beliefs after an infection sort of how an online classifier does and re-establish equilibrium.

Dybiosis, disrupting your commensals, can throw this system out of balance and trigger autoimmunity. This can also happen because of an infection.

Not true. Evidence is building that tau protein import to neurons activates the inflammasome, which causes cell death and local inflammation, if I skimmed this paper right:

https://www.nature.com/articles/s41586-019-1769-z

the cell death would presumably lead to the accumulation of more tau, a destructive feedback loop.

i read somewhere that tau shows up first, and that amyloid may be a natural response to the dysfunction caused by tau. tau is also implicated in several other degenerative diseases that lack amyloid abnormalities, like CTE and FTD. super interesting!

> The injectable molecule binds to misfolded tau and releases a radioactive signal researchers can visualize via PET scans.

I just want to say that this is really cool. Biology is such a weird field to work within.

I’m no biomed expert. But I recall earlier discussions that amyloid plaque is basically just misfolded proteins, which are hard to differentiate from prions by any meaningful definition.

Now I have no idea what Tau proteins are, but it sounds like they’re also a type of misfolded protein. So, to those more knowledgeable, how inaccurate would to be to say Tau proteins are basically prions too?

I'm also not an expert, but to me the critical distinction is that prions are contagious, that is they cause other proteins to misfold. You can have misfolded proteins that don't cause cascading problems.

> misfolded proteins, which are hard to differentiate from prions

Prions differ in that they are not merely misfolded, but they also catalyze more of themselves.

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