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.

Peter

6 comments:

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...

http://www.ncbi.nlm.nih.gov/pubmed/16337941

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...

Peter

Stan (Heretic) 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.

Peter

rkmarmot said...

Ken,

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

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