Thursday, June 25, 2009

Alzheimers and Tau proteins

This report on the "spreadable" nature of Alzheimers within the brain is in New Scientist and came to me via Glyn Wainwright on the THINCS forum. It's interesting in it's own right but I rather liked the related paper it linked to about the "contagious" nature of misfolded Tau proteins.

I think it would be reasonable to summarise the abstract as claiming that Tau proteins are non pathogenic structural proteins present inside, and essential to, normal nerve cells. Tau protein aggregates, which are abnormal products, "are observed" outside cells. My assumption is that, as healthy Tau are normally intracellular proteins, they have to be either excreted or exocytosed. Or the cell has to die to released them, before they can be found outside cells. The latter seems the more believable option.

Placing healthy monomer Tau proteins outside neuronal cells in culture does nothing. Placing Tau aggregates outside cells promotes endocytosis of those aggregates and, once endocytosed, the aggregates are directly toxic ("induce fibrillization") to the normal intracellular structural Tau. When this cell then dies it too will release it's abnormal Tau aggregates, which will go on to kill further recipient cells.

OMG its a locally contagious protein! Except it's not, it's a toxic substance which triggers the production of the same toxic substance from healthy tissue on contact.

Where do the original Tau aggregates come from? I suspect that Blaylock would argue they are shrapnel from the death of a neurone killed by catastrophic energy failure, induced by excitotoxins hitting glutamate-receptor sporting cells. This will no doubt involve hyperphosphorylation of Tau and all of the other exciting co factors for Alzheimers. Oh, and might be avoidable by supplying alternative energy molecules such as ketones. The shrapnel is itself neurotoxic and the product of its damage is more of the same neurotoxic shrapnel. This is a chain reaction and Alzheimers then becomes the neurological equivalent of Hiroshima. At this point Blaylock must be feeling quite justified in his views.

The obvious comparison, which is made in the abstract, is to prion proteins as featured in BSE.

If misfolded prion proteins are endocytosed, as Tau proteins are, and are themselves toxic to normal prion proteins, you then have the mirage of a contagious protein.

BSE can be induced in the brain of almost any recipient species by injecting a slurrry from the brain of a BSE case, which contains misfolded prion protein. But what is the trigger for the initial misfolding?

If I was prof Ebringer I might strongly suggest that the original trigger for prion misfolding is an autoimmune attack on myelin basic protein, or a similar structural protein, in the brain. We're not thinking neat and tidy apoptosis here, more like sudden death and spill your contents. Once the misfolding chain reaction is started the progression to BSE via more misfolding and cell death might then follow on, exactly as the Tau aggregates spread.

There is then no need for a contagious protein. In fact, it is easy to "spread" BSE by injecting the ash from incinerated BSE brain (600 deg C in the presence of oxygen. This means incinerated!!!). All you need is for the ash to damage the recipient brain enough to trigger protein misfolding and you have "transmitted" BSE using ash. Thoroughly formalin fixed brain tissue does the job rather better than fresh brain tissue too!

You really have to wonder what is going on here and the Tau "transmission" abstract makes Prof Ebringer and Russell Blaylock look pretty good as proposers of the correct triggers for the respective diseases to me.

Fascinating stuff.



Ken said...

'Ouroboros' has something to say about the dangers of autophagy at his blog, if I understand aright it's suggested that for neurons a rigorous fast could prove fatal.

Maybe fasting induced neuron death could spark a self-sustaining - and accelerating - wave of Tau proteins. Insulin resistance in the brain could have the same effect by starving neurons of energy?

After reading this post I am going to be doing only the gentle evening - overnight version terminated by break -fast after 18 hours at the most, and working up to that gradually.

Peter said...

Ken, I think even mild ketosis would be highly protective but insulin resistance would be catastrophic. Nerve cells do use insulin for glucose uptake and obviously insulin has functions in the brain beyond glucose control...

But it was the ash which got me. No control group as far as I could see. I just wonder what injecting any ash in to a mouse brain does.

In studies where there is a control group the BSE brain triggers BSE but normal brain tissue doesn't or, if it does, it is as rare as allergic encephalitis was after injecting animal brain tissue in to humans back in the early days of rabies treatment. You won't see this in a group of 5-10 mice. But pre formed abnormal prions are a different kettle of fish all together, particularly if the parallel holds with Tau proteins...


Stan Bleszynski said...

Re: ash in brain

Unless Purdy was right and it is the abnormal contents of manganese that displaces copper and triggers degeneration.

Also, the sudden cellullar chain reaction of death picture does not agree with the very slow progression of BSE and CJD.

Ken said...

"even mild ketosis would be highly protective"

Paleo hunters experienced hunger seasonally. The ketones would be gradually rising to a protective level as food got scarcer. Hence by a time food had to be gone without - in mid winter say - a high level of ketones would be present.

What happens if eat my fill right up until I fast for 24 hours?

With a full tank of glycogen ketones will be at a low level; by the time they rise the fast will be over. And if I've a degree of insulin resistance ill effects would be much worse.

I think fasting a day a week is unnatural. Better to do it the natural way: gradually. Roy Walford did a lot of abrupt fasting - one or two days a week I think - the neurological problem he developed could be entirely unrelated of course.

Peter said...

Stan, some of Purdy's ideas are quite interesting, especially the roll of sub sonic sound (one commercial assay uses this to amplify mis folded proteins, I lost the link when Red Flags went down). From the auto immune perspective I found suggestions, very poor quality, that OPs increase the blood brain barrier's permeability. So Purdy might have been looking at various aspects of whatever process is going on.

Re chain reactions, yes, tactical nukes rather than cityblasters might have been a better comparison.

I like your Furhman post BTW. I've got yet another half baked post based around the McDougall newsletter you sent me on the perils of veganism unless you buy his vegan DHA supplements. Summary, eat this way and die; unless you buy my supplements. Duhhh.

Ken, too much to say on this comment to do it now. I'll get to it but at the core is the type and reason for insulin resistance and what this does to energy supply to the brain.


rkmarmot said...


are you sure Walford engaged in acute, episodic caloric deprivation?

i had always thought that it he was into chronic caloric restriction/deprivatio.

Betsy said...

Thank you for your blog and all the time and thought you put into it. Here's some notes on Alzheimer's. I haven't read the other posts on it yet, I hope I'm not duplicating information.

Moreover, IL-6 induces phosphorylation of the tau protein
that is considered important in Alzheimer pathology.70

And from here:

The cytokines released by necrotic neurons induce further activation of microglia and astrocytes, resulting in positive feedback loops that can become independent of the original inducing molecules that are required to initiate inflammatory responses.

Inflammation and anesthesia

Some anesthetic agents have been shown to have anti-inflammation and immune-modulatory properties. Propofol, an intravenous anesthetic agent, was demonstrated that have neuroprotective effects. It is reported that propofol could inhibit LPS-induced microglial activation.

Peter said...

Hi Betsy, thanks for the links. Are you in mast cell research? I guess you might know that they are quite big players in adipocyte control too...


Betsy said...

I'm not in mast cell research, just have come across some stuff while trying to get better and remembered seeing Alzheimer's along the way and was wondering if it would connect to the tau protein at all. I have seen that hypoxia and lack of glucose can cause mast cell degranulation, I would like your opinion on how ketosis would affect that.

No, I didn't realize mast cells had anything to do with adipocyte control, so I started to look it up and so far have found this.

Adipose tissue as a dedicated reservoir of functional mast cell progenitors
(Yikes, does that mean the brain is a mast cell storehouse?)

Cytokines regulate development of human mast cells from hematopoietic progenitors

But I'm not sure what you mean about "adipocyte control". I had to work today and didn't have much time for looking into it.

Betsy said...

"We demonstrate that neither in sporadic nor in infectiously acquired or inherited human prion diseases can the activated forms of PERK and eIF2alpha be detected, except when concomitant neurofibrillary pathology is present; whereas the distribution of phosphorylated PERK correlates with abnormally phosphorylated tau in AD."

So AD is different from other prion diseases in that it involves endoplasmic reticulum stress.

One thing that can cause endoplasmic reticulum stress is viruses. Some viruses, such as EBV take advantage of heat shock protein and inhibit apoptosis, but some viruses will enhance apoptosis. So if LPS carries a virus to the brain, and if the virus is able to duplicate, cause endoplasmic reticulum stress, cause misfolded proteins, set UPR into motion, and cell death due to unresolved protein misfolding, could that be a possible explanation? There always does seem to be a metal involved, but I don't know where it would fit in with that hypothesis. Although it does seem that viruses like metals. Aluminum is frequently mentioned with AD, maybe the first insult was a vaccination containing aluminum and a virus????

Peter said...

My mast cell paper was this one

Re metals: I'm cautious. I'm also very suspicious that Fe and Cu accumulation in the liver of chronic hepatopathy cases may be adaptive. If you are saturated with PUFA which fail to provide the normal metabolic brake supplied by palmitate you may need some other source of insulin resistance to limit caloric overload. Fe of Cu generated H2O2 might provide that limiting signal. Al might be used by neurons. Of course for Al to be shown to be directly toxic we had a natural experiment several years ago in Devon (I think) where AlSO4 was accidentally dropped in to the water supply of a medium town. Is is a focus for early alzheoimers? Must have a quick google on that one...


Peter said...

Any follow up has been screwed up 100%


Betsy said...

"Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice."

ACCIDENT???? That's too bad.

Mast cells and weight gain? Theo Theoharides has some information on that but it was in Greek, but that study does explain the issue. It might explain why so many people in the Lyme forums experience extreme uncontrollable weight gain, as Lyme does somehow cause mast cell degranulation. Now I am wondering if it causes mast cell maturation, too.

While looking at the study that you linked I found this, I think it came up because I had seen cromolyn as having something to do with copper so I put that in a search along with who even knows what else.

"Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice."

I have to try to understand better what you said about Fe and Cu toxic stores in the liver, but it would be good news if clearing out PUFA could straighten things out. I am hoping. I had tried low carb many times but never really focused on getting the fat high enough to be able to make it through some difficulties it causes for me. Fear that it might be a wrong decision always made me back out. Right now I may have the horrible early morning leg cramps under control, headaches are becoming manageable, and joint pain is only transient. Other issues may come up, but I do trust that your research has shown that at the very least it's not a dangerous choice.

Betsy said...

Oh gee, I thought AlSO4 looked familiar, I had been conversing with someone about vaccine adjuvants. AlSO4 makes vaccines more "effective". (read:toxic)

I hope the accidental dump didn't include a virus.

In this paragraph in this book it's used for a vaccine I've never heard of.

But I think it's also used in an influenza virus. Maybe sometimes combined with squalene, as in Pandemrix.

Betsy said...

Your link about mast cells and obesity mentioned cromolyn, and as I said it brought copper to mind as I thought I remembered that cromolyn stops mast cell degranulation by chelating copper. I just found this study, I'm not sure what all it implies yet, and I'm not sure how it relates to tau protein misfolding, but it does relate to Alzheimer's and surprisingly to diabetes. I realize that they are saying Alzheimer's also entails what they call Type 3 diabetes, but I didn't expect to see it in this study.

Selective divalent copper chelation for the treatment of diabetes mellitus.
Cooper GJ1.
Author information
"Oxidative stress and mitochondrial dysfunction have been identified by many workers as key pathogenic mechanisms in ageing-related metabolic, cardiovascular and neurodegenerative diseases (for example diabetes mellitus, heart failure and Alzheimer's disease)."

Betsy said...

Was the Camelford incidence in 1988?

That was a bad year, look at this.

". This resulted in the prion
agent not being destroyed. It came to be delivered in cattle feed causing the epidemic of BSE
commencing in 1988. At its peak 3 000 heads of cattle per month were coming down with the
illness. A controversy arose whether BSE can be transmitted to humans through consuming beef."

I wonder where these two teenagers were from???
"Then an unusual form of Creutzfeldt-Jacob disease (CJD) was reported in two teenagers in 1995 in Britain.

And these 15 adults?

"By February 1997, fifteen cases were recorded in adult patients giving rise to public concern and a collapse in British beef exports."

Betsy said...

"These results suggest that when intracellular long-chain fatty acid concentrations are elevated, they may act directly on insulin-degrading enzyme to decrease insulin metabolism and alter insulin action in intact cells. This mechanism may contribute to the hyperinsulinemia and insulin resistance seen with elevated fatty acids and obesity."

"The link between hyperinsulinaemia and AD may be insulin-degrading enzyme (IDE). This enzyme degrades both insulin and amylin, peptides related to the pathology of type 2 diabetes, along with amyloid-beta peptide (Abeta), a short peptide found in excess in the AD brain."

Peter, what do you think of this "insulin degrading protein"?

Peter said...

Hi Betsy, insulin degrading enzyme is crucial to the half life of insulin in plasma and cells. As a rule of thumb as insulin activates insulin signalling it is handed to IDE for degradation. This is one reason a high cab diet triggers a high portal vein insulin but does not necessarily produce systemic hyperinsulinaemia if the vast majority of insulin is degraded in the liver so there is very little in the hepatic vein/caudal vena cava. Ultra low fat, as in "carbosis" facilitates the degradation. The roll of FFAs in insulin resistance is undoubtedly real and to find it within cells should come as no surprise.

The problem is that elevated FFAs and elevated insulin should never occur. As insulin rises FFAs should fall. The problems come when FFAs continue to leak from adipocytes, which is adipocyte size related. Your adipocytes get over distended by failing to resist insulin, as in omega 6s and Protons. That puts the guilt right at the feet of the cardiological community…..


Betsy said...

Thank you.

Betsy said...

I now am seeing that researchers are considering an insulin degrading enzyme antagonist for "treating" diabetes!

Peter said...

Oh, the depths of non-understanding have no limits!!!!!


Kyle Tengler said...

Came across this recently. ATP itself acts as a hydrotrope, increasing the solubility of proteins in cytosolic solution. If a cell had poor ATP production, dropping the concentration of ATP, it could increase the aggregation of proteins like Tau. Many studies have shown low ATP concentrations in the brain. It does not suggest causation, necessarily, but interesting to consider.