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April 5, 2010
Rapamycin for Alzheimer's?
Posted by Derek
Last summer a paper was published (PDF) showing rapamycin dosing appeared to lengthen lifespan in mice. (In that second link, I went more into the background of rapamycin and TOR signaling, for those who are interested). Now comes word that it also seems to prevent cognitive deficits in a mouse model of Alzheimer's.
The PDAPP mice have a mutation in their amyloid precursor protein associated with early-onset familiar Alzheimer's in humans, and it's a model that's been used for some years now in the field. It's not perfect, but it's not something you can ignore, either, and the effects of rapamycin treatment do seem to be significant. (The paper uses the same dose that was found to extend lifespan). The hypothesis is that rapamycin allowed increase autophagy (protein digestion) to take place in the brain, helping to clear out amyloid plaques.
What I also found interesting, though, was the rapamycin-fed non-transgenic control animals. In each case, they seem to show a trend for increased performance in the various memory tests, although they don't quite reach significance. This makes me wonder what the effects in humans might be, Alzheimer's or not. After that lifespan report last year, it wouldn't surprise me to find out that some people are taking the stuff anyway, but it's not going to be anywhere near enough of a controlled setting for us to learn anything.
This report is definitely going to start a lot of people thinking about experimenting with rapamycin for Alzheimer's - there are a lot of desperate patients and relatives out there. But together with that lifespan paper, it might also start some people thinking about it whether they're worried about Alzheimer's or not.
Comments (15)
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1. Marge on April 5, 2010 11:23 AM writes...
I did a quick search on that drug, also known as siroliums, and it looks like it's been investigated for about a dozen different indications (tuberous sclerosis, macular degeneration, a bunch of cancers, and transplant rejection). So why not one more?
Permalink to Comment2. Marge on April 5, 2010 11:24 AM writes...
Actually, that's sirolimus...sorry about the typo.
Permalink to Comment3. John on April 5, 2010 11:33 AM writes...
Re "it wouldn't surprise me to find out that some people are taking the stuff anyway, but it's not going to be anywhere near enough of a controlled setting for us to learn anything"
The only things I found from a quick search were reporting negative side-effects (inc. mood-related), presumably from high-dose transplant use.
The self-medicating internet community has been pretty rigorous in their DIY Phase IIs for some chemicals like afamelanotide, bremelanotide, etc. I sometimes wonder if it might be possible to get a grant for scientific outreach and data collection on these ad hoc messageboard studies.
Permalink to Comment4. RenegadeSci on April 5, 2010 11:58 AM writes...
If the mTor pathway up-regulates hsp, and improves protein folding, it could be of help. Since it's on the market, I would think it would be prescribed for Alzheimer's soon.
The current acetylcholinease inhibitors cause weight loss, nasuea, and confusion. Furthermore, they are toxic if you accidentally take an extra dose.
The thing with Alzheimer's is to improve quality of life. The immunosuppressant effects have to be taken into account, but this is great news.
I've been meaning to look up the mTor pathway in more depth. Researchers have had the same luck activating AMPK upstream of mTor with a certain small molecule.
AMP-activated Protein Kinase Signaling Activation by Resveratrol Modulates Amyloid- Peptide Metabolism* by Vingtdeut et al. shows similar results. My grandmother was taken by Alzheimer's in 1997, and died in 2004. Thankfully we seem to be making some progress.
Permalink to Comment5. lynn on April 5, 2010 12:08 PM writes...
As a post-transplant recipient of rapamycin (dose 2mg /day; i.e., while the mice got 2.24 mg/kg!) I'm intrigued with this study...of course and hoping for the potential benefit. But there are lots of side effects with rapamycin even at the relatively low levels I'm taking: slow healing, high triglycerides, high blood sugar - so I wouldn't recommend self-medication lightly.
Permalink to Comment6. Larry on April 5, 2010 3:29 PM writes...
Yeah let's scarf some down! Side effects must be minor....
http://en.wikipedia.org/wiki/File:MTOR-pathway-v1.7.svg
Permalink to Comment7. Kismet on April 6, 2010 9:58 AM writes...
Lynn, is the dose BSA-adjsuted? Normally, you cannot just translate animal doses to human ones. Does anyone know if this applies to rapamycin and what the therapeutic (immunosuppressive) doses in mice are?
Were the mice actually getting a regular dose or a "mega dose" of rapamycin?
Permalink to Comment8. retread on April 6, 2010 4:37 PM writes...
Before everyone gets carried away, remember that rapamycin's clinical use is as an immunosuppressant. Can anyone think of an immunosuppressant (glucocorticoids, tysabri, various monoclonal antibodies) without extremely serious side effects? Still, therapy for Alzheimer's is so minimal that it might be worth a shot.
Taking it to prevent aging based on what we know presently makes you a candidate for the Darwin awards.
Permalink to Comment9. lynn on April 6, 2010 7:54 PM writes...
@kismet The paper says the mice were fed the rapamycin and the estimated dose was, as I said, 2.24 mg/kg. No mention of oral bioavailability [~10% in rats, 14% in humans], PK, or, as you mention, albumin binding. Tried to find mouse immunosuppressive doses, but decided to stop reading since learning too much about possible adverse effents was getting a bit scary.
Permalink to Comment10. retread on April 6, 2010 9:57 PM writes...
Lynn: Remember that no one gets every side effect and some people get few or none. Sorry to scare you if I did, but the idea of taking a drug with the potential of serious side effects based only on evidence in animals to prevent aging is idiotic.
Consider the lack of benefit and serious harm suffered by women taking progesterone and estrogen to prevent vascular disease (the HERS study). Meta-analysis of case control studies (which were at least in people) predicted a huge benefit prior to the actual data.
Permalink to Comment11. Keith on April 7, 2010 11:46 AM writes...
Following on to "retreads" comment:
re: predictions of benefits related to case studies.
" extrapolation of data beyond observed experimental limits is highly problematic, due to the latent possibility of encountering an unexpected phenomenon just beyond the experimental limits".
My statistics lecturer made that point at university back in the 1950s!
Permalink to Comment12. Grace on August 20, 2010 10:45 AM writes...
My husband is in stage six of seven stages of Alzheimer's. What would he have to lose? I think they should test this drug on people in his condition.
Permalink to Comment13. folding doors on September 8, 2010 2:12 AM writes...
What would he have to lose? I think they should test this drug on people in his condition.
Permalink to Comment14. Cory on November 29, 2010 7:28 PM writes...
The article is pretty interesting and shows some promise I think. I had to read a few articles related to this stuff for school.
The transgenic mice did show significant decreases in amyloid beta desposits and Tau pathology. However, they still had significantly higher levels than non-transgenic mice, which is a consequence of the system. Really is no good mouse model to mimic the progression of Alzheimers.
Perhaps if you started treating with sirolimus during early stages you could prevent disease progression. At least seems worth a few primate/human trials.
It wouldn't be effective during late stages of Alzheimer's since there would be permanent damage to neurons.
Also have to consider that sirolimus blocks cytokine dependent proliferation of your immune cells so the whole use it to increase longevity is just stupid imo. Your immune system gets worse with age to begin with and mice live in a somewhat "sterile" environment so it's an unfair comparison. Besides the fact that we're going to be infected with various illnesses from time to time, sirolimus treatment would probably inhibit our anti-tumor response as well, which many of us are probably predisposed to (especially with age).
Though since the patent ran out and there are now generic forms available, I'm sure someone has started their daily regiment.
Permalink to Comment15. anonymous on December 30, 2010 10:54 AM writes...
Frustrating to have just learned about this today. My Grandmother died with Alzeimers (amoung other health problems) on August 20th 2010. It seems that it's been considered for testing with alzheimers for over a year. I wonder why this it hasn't had much development since and isn't in the mainstream media?
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