18 replies to this topic

[corb]

 

October 31, 2014 – New research that dramatically alters the prevailing theory of how Alzheimer’s disease develops has been published online today by Georgetown researchers in the journal Molecular Neurodegeneration.

The research also helps explains why some people with plaque buildup in their brains don’t develop dementia, and shows the potential of a cancer drug to combat the disease.

“This study suggests a completely new way to look at Alzheimer's that might alter the way we study the disease, screen for it and ultimately treat it,” says the study’s senior investigator, Charbel E-H Moussa, MB, PhD, of Georgetown University Medical Center.

NEURONAL DEATH

Moussa co-authored the study with researchers from Capital Medical University in Beijing, China and Merck Research Laboratories, which provided funding for the study.

The research team discovered that malfunctioning tau, not amyloid-beta plaque, is the seminal event that spurs neuron death in disorders such as Alzheimer’s disease.

Neuronal death occurs when tau, a protein found inside neurons, fails to function, the study shows.

GENES AND AGING

The role of tau is to provide a structure – somewhat like a train track  – inside brain neurons that allows the cells to clear accumulation of unwanted and toxic proteins or “garbage.”

Malfunctioning tau can occur because of errant genes or through the normal aging process. As some individuals grow older, tau can malfunction, while enough normal tau remains to help clear the garbage.

“That explains the confusing clinical observations of older people who have plaque build-up, but no dementia,” Moussa explains.

COMMON CULPRIT

Moussa is an inventor on a Georgetown University patent application for use of nilotinib, a drug approved to treat cancer, as a therapeutic approach in neurodegenerative diseases.

The study shows that nilotinib can help the neuron clear the garbage if some functional tau remains.

“This drug can work if there is a higher percentage of good-to-bad tau in the cell,” Moussa says, adding that many dementias have malfunctioning tau and no plaque accumulation, such as a type linked to Parkinson’s disease. “The common culprit is tau, so a drug that helps tau do its job may help protect against progression of these diseases.”

 

http://gumc.georgeto...elopment-Theory

[Mind]

Not sure if this is such a big breakthrough or really gets to the heart of Alzheimer's more than other theories. A-beta plaque definitely seems to be a player in the grand scheme of this disease. The Mankato nun study seemed to point toward lifestyle factors that prevented the nuns from developing Alzheimer's even though they had plaque build up. They remained active into old age, including mental activity, and maintained a good diet. I have argued elsewhere that the plasticity and adaptability of the brain (use it or lose it) helps stave off dementia, even with plaque build up or tau malfunction.

 

Bottom line is, staving off dementia without removing plaque would be great, but I would still want that junk out of my brain.

[Kalliste]

The recent lifestyle take on Alz also indicates that lifestyle is the big player. Of course we need to clean out all the gunk, this is another medical approach that works to slow down and not repair. As usual.

[resveratrol_guy]

Can anyone enlighten me as to why this seems to have been ignored, i.e. low-dose nilotinib (and bosutinib?) upregulates autophagy to the extent that early-to-moderate taupathy could be substantially reversed? User zen actually posted this here back in 5/2013.

 

Follow me on this for a second... if we're already self-experimenting with something like dihexa which had apparently never before been tested on humans, then nilotinib seems like a lower risk level (after all, it's a human leukemia drug, and we're talking about low doses here) for a potentially similar result (getting smarter, but this time by cranking up neuronal autophagy). But I can't find the "this doesn't work" thread here on Longecity or anywhere else, for that matter. One reason might be patent issues, but that never stopped third world labs from synthesis. So I'm still stumped. Of course, maybe that's because I need more nilotinib...

 

[Darryl]

Preventative use of nilotinib is unlikely given high cost (its a biologic) and pretty severe side effects (>10% incidence of headache, nausea, rash, itchiness, hair loss, dry skin, muscle aches, fatigue), though I'd be very interested in a trial in early cognitive decline.

 

Among the numerous compounds that induce autophagy in vitro, I think most attractive at the moment are approved, centrally active, negligible adverse effect small molecules like rilmenidine, which David Rubinsztein has advised at least one Huntington's carrier to take in the hope of delaying that disease's onset. Some other options are presented in:

 

Renna, M., Jimenez-Sanchez, M., Sarkar, S., & Rubinsztein, D. C. (2010). Chemical inducers of autophagy that enhance the clearance of mutant proteins in neurodegenerative diseases. Journal of Biological Chemistry, 285(15), 11061-11067.

Edited by Darryl, 26 January 2015 - 09:25 PM.

[tunt01]

 

Among the numerous compounds that induce autophagy in vitro, I think most attractive at the moment are approved, centrally active, negligible adverse effect small molecules like rilmenidine, which David Rubinsztein has advised at least one Huntington's carrier to take in the hope of delaying that disease's onset. 

 

 

The risk/reward on something like lithium, intermittent fasting, and exercise, which all upregulate autophagy, is probably way higher than nilotinib.  But that won't stop pharma from trying to repurpose a drug for a new indication and make money off it.

Edited by prophets, 26 January 2015 - 11:23 PM.

[corb]

 

Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer's disease.

The severity of tau pathology in Alzheimer's disease brain correlates closely with disease progression. Tau immunotherapy has therefore been proposed as a new therapeutic approach to Alzheimer's disease and encouraging results have been obtained by active or passive immunization of tau transgenic mice. This work investigates the mechanism by which immunotherapy can impact tau pathology. We demonstrate the development of Alzheimer's disease-like tau pathology in a triple transgenic mouse model of Alzheimer's disease and show that tau/pS422 is present in membrane microdomains on the neuronal cell surface. Chronic, peripheral administration of anti-tau/pS422 antibody reduces the accumulation of tau pathology. The unequivocal presence of anti-tau/pS422 antibody inside neurons and in lysosomes is demonstrated. We propose that anti-tau/pS422 antibody binds to membrane-associated tau/pS422 and that the antigen-antibody complexes are cleared intracellularly, thereby offering one explanation for how tau immunotherapy can ameliorate neuronal tau pathology.

 

http://www.ncbi.nlm....pubmed/25085375

Edited by corb, 26 January 2015 - 11:30 PM.

[resveratrol_guy]

@ Darryl: Brilliant link! I obviously have a lot to study here that I was not even aware of.

 

@ prophets: I didn't know lithium upregulated autophagy, inasmuch as it's been rumored to prevent white matter atrophy. Thanks for the research tip.

 

@ corb: This is the first I've heard of Alzheimer's immunotherapy. It suggests that there are really 2 problematic manifestations of tau decay: (1) intraneuronal, which is compensated for by autophagy to some extent and (2) extraneuronal, which is exposed to macrophages and therefore, in theory, your pS422 antibody. Thanks for this. I have a lot to read!

[Luminosity]

Mind has a good point.  

 

I've written about my theory on dementia/Alzheimers and natural approaches to it, elsewhere on this forum.  Anyone who wants to look into could Google Longecity.org, my name and the subject matter.  Hopefully the relevant material will come up.  

[resveratrol_guy]

So after digging into this whole proautophagy approach to Alzheimer's, I've become semi-convinced that rapamycin derivatives are the way to go. Darryl's article mentioned lithium and sodium valproate, but the former is highly dose-dependent and the latter actually accelerated Alzheimer's in a clinical trial circa 2005. (The paper did note that the researchers pushed the limits of what the patients could safely consume; perhaps they mostly cured the tauopathy but overdid the autophagy to the point of mass neuronal self-digestion. So I'm not convinced that valproic acid derivatives are, a priori, ineffective.)

 

Anyway, the rapamycin pictures looks more promising. On the safety side, several derivatives have already been FDA approved for treating various cancers including some forms of brain cancer, so at least their side effects are well documented at this point. The only major negative to mTOR inhibition via rapamycin and friends is the disruption to the mTORC2 pathway, which involves blood sugar regulation. As a result, rapamycin at therapeutic doses for Alzheimer's would probably promote insulin resistence. However, we have plenty of compounds and natural substances (e.g. bitter gourd, coconut oil, etc.) to combat that problem. And the bottom line is that it extended life in mice, diabetes or not. It was pointed out elsewhere here that the lifespan extension may have been entirely due to cancer suppression, but whatever; it worked.

 

So without further delay, I found some preprint articles pertaining to precisely this strategy of combatting and potentially reversing the tauopathy that the OP has implicated as the main offender in AD. (Sorry there is no published full text yet, but I thought I should post these so y'all can get ahead of the press; some offer a weird preprint full text option, whatever that means). I can see a dihexa-ish group buy playing out if these drafts pass peer review and/or final typo checking.

 

https://www.ncbi.nlm...pubmed/25408212

https://www.ncbi.nlm...pubmed/25661995

https://www.ncbi.nlm...pubmed/25596147

https://www.ncbi.nlm...pubmed/25481271

 

keywords: rapamycin, temsirolimus, everolimus, sirolimus, wogonin

 

...what do you know? The aerial parts of the popular nootropic bacopa monieri (a marsh plant) contain the putative anticancer/antialzheimer's phytochemical, wogonin: https://www.ncbi.nlm...pubmed/15022161

Edited by resveratrol_guy, 14 February 2015 - 06:28 AM.

[ceridwen]

I read somewhere on the forum that Bacopa can't be taken with other supplements as it has an adverse effect on blood pressure. Could anyone enlighten me as to whether this really is true?

[resveratrol_guy]

It's only adverse if your blood pressure is already too low:

 

https://www.ncbi.nlm...pubmed/22447676

https://www.ncbi.nlm...pubmed/21762768

 

Full text is paywalled. Note that those studies are from Thailand, so you might want to confirm with sources from more regulated countries.

 

"Brahmi reduces blood pressure partly via releasing nitric oxide (NO) from the endothelium, with additional actions on vascular smooth muscle Ca(2+) homeostasis"

 

"Increased [cerebral blood flow] with B. monnieri may account for its reported procognitive effect, and its further exploration as an alternative nootropic drug is worthwhile." (Sounds similar to vinpocetine in this one regard.)

 

This is in stark contrast to rapamycin, which downregulates NO via nitric oxide synthase. Because macrophages use NO as a poison gas cloud to attack pathogens, rapamycin also downregulates the immune system and, unsurprisingly, has been found to impair endothelial health. Obviously, it's all a question of tradeoffs. References:

 

https://www.jstage.j...6/32_6_988/_pdf

http://cardiovascres.../3/563.full.pdf

 

"Recent evidences have demonstrated an increased incidence of late thrombosis of rapamycin-eluting stents after the discontinuation of dual antiplatelet therapy. These effects may be caused by the long-term endothelial dysfunction that is now well documented after the implantation of rapamycin-eluting stents." Translation: if you use rapamycin analogs to attempt to prevent or reverse tauopathy, make sure to take an aspirin, vitamin K2 MK4 and MK7, olive oil, raw cacao (and perhaps bacopa) etc. to prevent fatal thrombosis. This isn't a theoretical risk: rapamycin increases fatal thrombotic events when used in cancer therapy, despite its prosurvival advantages otherwise. (Sorry I can't find the study at the moment, but it's on Google somewhere.)

 

One other word of warning: it has been said in numerous papers that rapamycin acts on both mTORC1 and mTORC2 via mTOR, but only the mTORC1 pathway is anticancer, so it would be desirable to find an inhibitor of mTORC1 alone; indeed, this might ameliorate some of the prodiabetic or other side effects. But in some cases (not sure how often) mTORC2 is also anticancer, so rapamycin analogs might be close to the best we can do for now insofar as cancer is concerned (but mTORC1 alone might be more appropriate for treating dementia because we don't want to damage the cerebral endothelia): "The cytostatic effect of mTORC2 down-regulation in proliferating mast cells was determined to be via inhibition of cell-cycle progression. Because mTORC2 was observed to play little role in the homeostasis of differentiated, nonproliferating, mature mast cells, these data provide a rationale for adopting a targeted approaching selectively inhibiting mTORC2 to effectively reduce the proliferation of mast cells associated with inflammation and disorders of mast cell proliferation while leaving normal differentiated mast cells largely unaffected." Nevertheless mTORC1-only inhibitors are grossly unproven at the moment.

 

http://www.bloodjour...so-checked=true

 

Edited by resveratrol_guy, 14 February 2015 - 07:45 PM.

[Brett Black]

The only major negative to mTOR inhibition via rapamycin and friends is the disruption to the mTORC2 pathway, which involves blood sugar regulation.

So immunosuppression isn't a problem at the doses you're considering?

[resveratrol_guy]

 

So immunosuppression isn't a problem at the doses you're considering?

 

 

Sorry if I glazed over this. Clearly, immunosuppression is a serious issue, particularly among chemotherapy patients receiving rapamycin analogs, considering that they are likely immunocompromised to begin with. OTOH we can compensate for this problem by other means, for example, carbon 60 olive oil (chronically) and GCSF or antibiotics (acutely). Various mushroom extracts are likely supportive as well, not to mention a litany of other clinically proven immune boosters. Nevertheless, thank you for raising an important point which should not be neglected, especially because we're talking about Alzheimer's patients who, like their cancer counterparts, are generally not in the best of health anyway.

 

As to what specific doses induce how much immunosuppression, diabetes, or autophagy, I have no specific data, and I suspect that the answer is unfortunately of the watch-and-wait variety.

 

P.S. On further analysis, the immunosuppression might actually enhance the neuroprotective effect, infectious hazards notwithstanding, if the 2003 paper linked below is accurate. It purports to demonstrate that wogonin is neuroprotective due to its suppression of microglia proinflammatory signalling (independent of the question of autophagy). It does make some sense that saving dysfunctional neurons might be preferable to killing them while producing inflammation in the process. In other words, better to have a somewhat demented neuron, than no neuron at all and lots of garbage everywhere (unless that neuron is metastatic cancer, which is very rare but possible, of course).

 

I'm starting to think that wogonin is a poor man's rapamycin: autophagy and disinflammation without the accessibility problem of highly regulated cancer drugs. It comes from Scutellaria baicalensis, which Wiki says is easily confused with similar and potentially toxic plants, so be careful.

 

http://www.fasebj.or...057fje.full.pdf

 

Edited by resveratrol_guy, 15 February 2015 - 05:28 AM.

[Luminosity]

Whoever wrote that comment on my post is a jerk, and a coward.  Why don't you post that under your name? 

Edited by Luminosity, 15 February 2015 - 05:35 AM.

[resveratrol_guy]

This thread prompted me to learn about the state of the art in therapeutic approaches to Alzheimer's immunotherapy, which should augment autophagy. But I don't want to pollute this thread, so I put it here.

[Logic]

Preventative use of nilotinib is unlikely given high cost (its a biologic) and pretty severe side effects (>10% incidence of headache, nausea, rash, itchiness, hair loss, dry skin, muscle aches, fatigue), though I'd be very interested in a trial in early cognitive decline.

 

Among the numerous compounds that induce autophagy in vitro, I think most attractive at the moment are approved, centrally active, negligible adverse effect small molecules like rilmenidine, which David Rubinsztein has advised at least one Huntington's carrier to take in the hope of delaying that disease's onset. Some other options are presented in:

 

Renna, M., Jimenez-Sanchez, M., Sarkar, S., & Rubinsztein, D. C. (2010). Chemical inducers of autophagy that enhance the clearance of mutant proteins in neurodegenerative diseases. Journal of Biological Chemistry, 285(15), 11061-11067.

 

Note that the dosage that was effective in the Parkinson's trial was much lower at 150-300mg per day.
You are much more likely to have side effects at the 'up to 800 milligrams' used for cancer.

Some of the latest research have rigid Parkinson's  talking and going to the kitchen to get something to eat!

http://www.techtimes...stage-trial.htm

 

https://www.newscien...ent=NewTemplate

 

 

I have a friend who's mom has Parkinson's, who is very interested in Nilotinib.
Anything that clears misfolded proteins from ones brain has my attention!?

Edited by Logic, 11 December 2015 - 02:42 PM.

[Logic]

Nilotinib group buy:

http://www.longecity...p-buy/?p=756872

[Logic]

Nilotinib group buy:

http://www.longecity...ndpost&p=765364

 

If you are interested in acquiring Nilotinib prices are as follows:

• Nilotinib $ 8.61 per gram.
• 3rd party testing: $ 600 divided by the number of people that commit to the buy.
• 6 people have committed to the group buy so far, so $600/6 = $ 100 each. I am working on 6 people. ie: add $100 to the above cost.
• Postage from the testing lab has to be added and will differ depending on you location.

So far the following people have committed to the group buy:

• resveratrol_guy                   100 g     $ 961.00  
• ceridwen                              30 g      $ 358.30      
• Logic                                    30 g      $ 358.30     
• noot_in_the_sky                  50 g       $ 530.50
• LongLife                              100 g     $ 961.00
• Der Springende Punkt         20 g       $ 272.20 

Persons who has paid so far:

• resveratrol_guy
• Logic
   

If you are interested please PM me with your address and I will supply my Paypal Email address and the cost of postage from the lab and the lab's details.

• If a minimum of 200 grams is not reached I will refund those who have paid.
• If the number of people is less than 6: More money will have to be paid in for testing.
• If the number of people is more than 6: I will refund the difference.

Timeline:

• Arrival at testing lab after payment of the supplier: 4-6 working days.
• Testing and splitting/packaging for end destination: 5-7 working days.
• Postage to final destination:  unknown.

I am holding thumbs that the buy will be successful, so do contact anyone you think may be interested to bring the cost down as much as possible.