5 ms·

> However, in the words of neurologist David Pérez of Madrid’s Hospital 12 Octubre, thinking that these proteins are responsible for Alzheimer’s is like arrivin

> However, in the words of neurologist David Pérez of Madrid’s Hospital 12 Octubre, thinking that these proteins are responsible for Alzheimer’s is like arriving at the scene of a crime and believing the blood committed murder. I keep reading so much about the mis-folded proteins that it's easy to forget that's not the target? But at the same time, I can't help but think that if we stop the mis-folding we stop the problem? Or am I just thinking about it all wrong?

colechristensen 5y ago
There is evidence that the misfolding may be a side effect not a cause.
virgilp 5y ago
> arriving at the scene of a crime and believing the blood committed murder. It's more like "believing the death was caused by loss of blood" though, right? As in, it's not completely unreasonable to believe that if you could somehow stop (& compensate) the loss of blood in a timely manner, the person might live, even with a bullet in their body.
- inciampati 5y ago
  If you want to specify the metaphor more, it would be like believing that the blood clots committed murder. The protein aggregations apparently serve the same purpose, and are often generated in response to damage/infection.
kinjba11 5y ago
The 'amyloid hypothesis' as the protein being the cause of Alzheimer's has been the most popular for a few decades, so it's not surprising you've read so much about it. But there hasn't been much success in drugs targeting the protein. New evidence suggests that there could be an underlying cause. I'm a fan of the theory that bacteria/viruses are a cause and that the proteins we see are an overkill immune response to that (wouldn't be the first time - influenza/covid kill some not directly but via the immune system over-doing it). See https://www.nature.com/articles/d41586-018-05719-4 https://www.nature.com/articles/d41586-018-05719-4 for more details.
- dnautics 5y ago
  when i was a grad student in an amyloid lab (2009-ish) we were already doubting the amyloid hypothesis. Not so much the PIs. It's kind of wierd to see these ideas finally catching hold today. But when the grant money is coming in, you're gonna push your hypothesis hard. That said, IMO we really don't know. I worked on figuring out how to make these experiments more reproducible. My paper is cited a TON, but whenever I peek into the field, people are still are using shitty techniques, even the papers citing me.... Feels like "you didn't read the paper, did you?".
- EMM_386 5y ago
  > I'm a fan of the theory that bacteria/viruses are a cause and that the proteins we see are an overkill immune response to that That would be ... bad ... given that we just had a lot of the world exposed to Covid, and then we just vaccinated everyone to ramp up the immune system.
  - vmception 5y ago
    Thats what happened last time with encephalitis lethargica
  - atatatat 5y ago
    Correct.
tejtm 5y ago
Life almost by definition is not the lowest energy state matter can exist at. Thus living proteins may need some extra energy care and maintenance to maintain their functional form. Without this active input, they may relax into a form that from one perspective is "mis-folded" but from another perspective is just the natural lower energy state the collection of atoms is expected to be found in if nothing is maintaining it. So maybe instead of "stop misfolding" it is provide adequate maintenance infrastructure and budget. But the maintenance workers (mitochondria) have a much more active life than the sedentary (brain) cells they inhabit and have suffered through many cell divisions each with their accumulation of errors till at some point just like all us worker drones, have no fscks left to give.

colechristensen 5y ago

There is evidence that the misfolding may be a side effect not a cause.

virgilp 5y ago

> arriving at the scene of a crime and believing the blood committed murder. It's more like "believing the death was caused by loss of blood" though, right? As in, it's not completely unreasonable to believe that if you could somehow stop (& compensate) the loss of blood in a timely manner, the person might live, even with a bullet in their body.

inciampati 5y ago
If you want to specify the metaphor more, it would be like believing that the blood clots committed murder. The protein aggregations apparently serve the same purpose, and are often generated in response to damage/infection.

kinjba11 5y ago

The 'amyloid hypothesis' as the protein being the cause of Alzheimer's has been the most popular for a few decades, so it's not surprising you've read so much about it. But there hasn't been much success in drugs targeting the protein. New evidence suggests that there could be an underlying cause. I'm a fan of the theory that bacteria/viruses are a cause and that the proteins we see are an overkill immune response to that (wouldn't be the first time - influenza/covid kill some not directly but via the immune system over-doing it). See https://www.nature.com/articles/d41586-018-05719-4 https://www.nature.com/articles/d41586-018-05719-4 for more details.

dnautics 5y ago
when i was a grad student in an amyloid lab (2009-ish) we were already doubting the amyloid hypothesis. Not so much the PIs. It's kind of wierd to see these ideas finally catching hold today. But when the grant money is coming in, you're gonna push your hypothesis hard. That said, IMO we really don't know. I worked on figuring out how to make these experiments more reproducible. My paper is cited a TON, but whenever I peek into the field, people are still are using shitty techniques, even the papers citing me.... Feels like "you didn't read the paper, did you?".
EMM_386 5y ago
> I'm a fan of the theory that bacteria/viruses are a cause and that the proteins we see are an overkill immune response to that That would be ... bad ... given that we just had a lot of the world exposed to Covid, and then we just vaccinated everyone to ramp up the immune system.
- vmception 5y ago
  Thats what happened last time with encephalitis lethargica
- atatatat 5y ago
  Correct.

tejtm 5y ago

Life almost by definition is not the lowest energy state matter can exist at. Thus living proteins may need some extra energy care and maintenance to maintain their functional form. Without this active input, they may relax into a form that from one perspective is "mis-folded" but from another perspective is just the natural lower energy state the collection of atoms is expected to be found in if nothing is maintaining it. So maybe instead of "stop misfolding" it is provide adequate maintenance infrastructure and budget. But the maintenance workers (mitochondria) have a much more active life than the sedentary (brain) cells they inhabit and have suffered through many cell divisions each with their accumulation of errors till at some point just like all us worker drones, have no fscks left to give.