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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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February 7, 2012

Tau Spreads On Its Own?

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Posted by Derek

I've been meaning to mention the very interesting work that's shown up on tau protein in Alzheimer's. That's generally taken a back seat to amyloid in the protein-pathologies-of-Alzheimer's derby, but no one has been able to rule it out as a causative event, either. And the progress of tau pathology through the brain is quite suggestive - it tends to start in one region (the entorhinal cortex) and spread from there. The question is, what's driving that process? Is it tau itself spreading, or perhaps something inside the cell that causes tau problems is spreading, or is it some set of external conditions (that lead to tau pathologies) which is spreading?

This latest work goes a good way towards settling that question. (Here's one group's paper in PLoS One; the other paper in Neuron doesn't seem to be up yet, which has caused some controversy). The researchers in question engineered mice that express human tau protein localized to the entorhinal cortex (EC). They then sat back and watched what happened, taking sample along the way.

And what happened was a spectacular result. They found human tau in the EC initially, as expected. But over time, it began to show up in brain regions that are synaptically connected to the EC, and then it spread to the regions that are connected to those. This is human tau protein, remember - the only cells in the brains of these mice that should be able to make it are in the EC. In other words, the protein itself appears to be spreading from neuron to neuron, apparently through the synaptic junctions:

In general, our NT mouse model replicates the spatial and temporal aspects of the earliest stages (I–III) of Braak staging of tauopathy in Alzheimer's disease. We have demonstrated that tau pathology initiating in the EC can spread to other synaptically connected brain areas as the mice age, supporting the idea that AD progresses via an anatomical cascade as opposed to individual events occurring in differentially vulnerable regions.

They also now have a very interesting (and potentially very useful) mouse model of Alzheimer's pathology. There are still a huge number of open questions about Alzheimer's, don't get me wrong. But this is a real advance, in a field that doesn't see as many of those as everyone would like. Now to figure out how that protein is spreading (How's it excreted from the cell? How's it taken up by the next ones in line?) and why.

Comments (21) + TrackBacks (0) | Category: Alzheimer's Disease


COMMENTS

1. luysii on February 7, 2012 10:34 AM writes...

This is all very nice, and any help we can get in understanding Alzheimer's disease (and dementia in general) is welcome. However, the following should be kept in mind.

For the vast lot of you who are NOT neuropathologists: Alzheimer's disease is characterized by two findings on microscopy -- senile plaques outside neurons, and neurofibrillary tangles (made of hyperphosphorylated tau protein) inside neurons. It invariably hits an area of the brain called the hippocampus the hardest. The hippocampus is known to be involved in memory, and memory loss is a prominent and early symptom of Alzheimer's disease (trust me).

Frontotemporal dementia is different pathologically.
[ Neuron vol. 60 p. 534 '08 ] Frontotemporal dementia due to tau mutations DOES NOT HAVE SENILE PLAQUES. The pathology (neurofibrillary tangles) first occur outside the hippocampus. [ Neuron vol. 66 p. 633 '10 ] 40 different mutations in tau have been found in frontotemporal dementia, but no tau mutations have been in Alzheimer's.

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2. milkshake on February 7, 2012 10:45 AM writes...

I remember an interesting autopsy study done on nuns published about 5 years ago. Someone was studying mental state of nuns in convents, and tested for mental decline of these nuns over decades, and apparently convinced his test subjects to donate their brains to science. The advantage of dissecting nuns is that they are closest to lab animals - strictly defined and regimented life, well-documented medical history etc. His surprising finding was that the occurrence of amyloid plaques was not a sufficient factor for developing dementia - there were nuns who stayed mentally sharp to their 90s and they turned out to have lots of plaques in their brains. His theory was that a combination of plaques with other underlying pathology, such as accumulated damage from microscopic strokes was necessary to cause dementia.

So it looks like amyloid plaques might be a trigger but tau is the actual driver

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3. PPedroso on February 7, 2012 1:29 PM writes...

@Milkshake, the problem is that you can have amyloid plaques without Alzheimer but you cannot have Alzheimer without amyloid plaques.

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4. otis on February 7, 2012 3:01 PM writes...

@luysii thanks for the insight. I am NOT a neuropathologist but a chemist and I apologize if I turn this into a 'with living with dementia/Alzheimers discussion. I have a family member with dementia/Alzheimers. She is in an excellent assisted living commuity and doing very well. Although saddening to watch her progress in her dementia, scientifically, her behavioral changes were fascinating. Even friends colleagues who are struggling with older parents, each have a different behavior story (some are very quiet lose their ability to speak and wander off, for example). So my question, are you aware if there are any clinical behavorial differences in those that have Frontotemporal dementia versus those have these senile plaques outside neurons, and neurofibrillary tangles inside neurons in/around the hippocampus?
Just curious.

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5. Mel Harte on February 7, 2012 4:08 PM writes...

"How does the tau protein proliferate?" is by far the most compelling question for me. The answer will probably greatly influence the evolution of treatment. Is the protein somehow co-opting cell RNA to replicate itself once inside the new neuron? Are there previous examples of such possibilities with non RNA proteins?
I'll stay tuned...

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6. Scott on February 7, 2012 7:01 PM writes...

One novel thought is that tau proteins spread throughout the brain similar to fictional ice-nine, acting as seed crystals which irreversibly alter the conformation of adjacent proteins to create the distinction neurofibrillary tangles within neurons. Until someone comes up with a better idea this is as valid as any. From Wikipedia:

Ice-nine is a fictional material appearing in Kurt Vonnegut's novel Cat's Cradle. It is supposed to be a more stable polymorph of water than common ice (Ice Ih) which instead of melting at 0 degrees Celsius (32 degrees Fahrenheit), melts at 45.8 °C (114.4 °F). When ice-nine comes into contact with liquid water below 45.8 °C (which is thus effectively supercooled), it acts as a seed crystal, and causes the solidification of the entire body of water which quickly crystallizes as ice-nine. A global catastrophe involving freezing the Earth's oceans by simple contact with ice-nine is used as a plot device in Vonnegut's novel.

Vonnegut came across the idea while working at General Electric:

The author Vonnegut credits the invention of ice-nine to Irving Langmuir, who pioneered the study of thin films and interfaces. While working in the public relations office at General Electric, Vonnegut came across a story of how Langmuir, who won the 1932 Nobel Prize for his work at General Electric, was charged with the responsibility of entertaining the author H.G. Wells, who was visiting the company in the early 1930s. Langmuir is said to have come up with an idea about a form of solid water that was stable at room temperature in the hopes that Wells might be inspired to write a story about it. Apparently, Wells was not inspired and neither he nor Langmuir ever published anything about it. After Langmuir and Wells had died, Vonnegut decided to use the idea in his book Cat's Cradle.[1]

The fictional ice-nine should not be confused with the real-world ice polymorph Ice IX, which does not have these properties.

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7. luysii on February 7, 2012 7:32 PM writes...

Well maybe ice-9 is science fiction, but it's nearly identical to an idea that won Stanley Prusiner the Nobel prize. Prions are basically a different disposition of the protein atoms in space (e.g. conformation), which cause other proteins to adopt the same disposition, causing masses of insoluble junk. They cause Jakob Creutzfelt disease, mad cow disease, etc. etc.

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8. Morten G on February 8, 2012 6:44 AM writes...

Scott seems to be missing the point of the paper which is that human tau (not mouse tau) showed up in cells where it shouldn't be expressed based on the promoter sequence.

ice-9 is however how scrapie, BSE (mad cow disease), kuri-kuri, and (variant) Jacob-Kreutzfeldt disease works.

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9. Ginsberg on February 8, 2012 10:23 AM writes...

Isn't Prusiner still pushing the idea of a "protein X"? an as-yet unidentified cellular protein that enables the conversion of PrPC to PrPSc by bringing a molecule of each of the two together into a complex.

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10. Scott on February 8, 2012 10:59 AM writes...

I was extrapolating this from the PLoS One article (below) and the proposition that tau may be acting as a "contagious protein" in AD, analogous to the spread of synuclein in Parkinson's Disease.

"Our data demonstrate propagation of pathology from the EC and support a trans-synaptic mechanism of spread along anatomically connected networks, between connected and vulnerable neurons."

Curcumin, one of my favorite spices and a natural phenol, interestingly seems to be able to block the hyperphosphorylation of these tau proteins and the progression of related diseases. Perhaps hyperphosphorylation is a final common pathway which makes tau proteins "contagious", but their spread is still mystifying.

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11. luysii on February 8, 2012 1:20 PM writes...

Not sure if he's still pushing it. I can't find a reference to protein X in my notes later than 2003. Laura Manuelidis at Yale doesn't believe Prusiner (despite the Nobel) and says that protein X sounds awfully like a virus to her.

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12. sgcox on February 9, 2012 6:10 AM writes...

interesing paper in Nature:
http://www.nature.com/nature/journal/v482/n7384/pdf/nature10821.pdf

It shows direct link between amyloid processing and tau phosphorylation in cultured cells.

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13. sct on February 9, 2012 7:55 AM writes...

To PPedroso,
On your point that you can't have AD without b-amyloid,it is because that is how AD is artificially defined.AD is defined as dementia with tau tangles and b-amyloid plaque.All other dementia with tau tangles or tau aggregation but without b-amyloid ,is by definition not AD.If one were to exclude b-amyloid from the definition,then all the dementia diseases with tau tangles or tau aggregation ,such as FTD,PSP, CBD etc are known as tauopathy

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14. sct on February 9, 2012 7:56 AM writes...

To PPedroso,
On your point that you can't have AD without b-amyloid,it is because that is how AD is artificially defined.AD is defined as dementia with tau tangles and b-amyloid plaque.All other dementia with tau tangles or tau aggregation but without b-amyloid ,is by definition not AD.If one were to exclude b-amyloid from the definition,then all the dementia diseases with tau tangles or tau aggregation ,such as FTD,PSP, CBD etc are known as tauopathy

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15. Scott on February 9, 2012 6:05 PM writes...

Very timely and relevant to the tau protein discussion, bexarotene has some interesting effects in AD patients.

http://www.dana.org/news/features/detail.aspx?id=35464

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16. sct on February 12, 2012 1:57 AM writes...

The Dana article on bexarotene broke away from the traditional view that b-amyloid is the key driver of AD ,but still expressed the popular view that b-amyloid triggers tau aggregation at pre-clinical stage.Actually the evidence of such view is not convincing.Most scientists cited a paper by Joseph Price et al as basis for such evidence but the reasoning put forward by the arthors is quite subjective.
the authors put foward the following reasoning:
Healthy aging subjects had different degree of tau tangles in hippocampus correlated with age,but demented subjects had more tau tangles correlated to neuritic plaque(b-amyloid+tangles). Because genetic mutations that produce excessive b-amyloid also produce more tau tangles that lead to familial AD,so the correlation of tau and b-amyloid must likewise be b-amyloid triggering excessive tau tangles that lead to late onset AD.
this reasoning cannot hold upon scrutiny:
The causative link between genetic mutation and excessive production of b-amyloid which in turn triggers tau tangles has never been solidly established.if at all the scientific evidence showed otherwise.In the case of mutated presenilin gene in one of the familial AD,the gene was shown not producing more b-amyloid, but actually impaired the lysosome, the cell's garbage clearing system ,causing both undisposed tau tangles and b-amyloid to cummulate,so the increase in tau tangles was not related to b-amyloid.This may well explain all the other genetic causes of AD.If genetic ADs are not cuased by b-amyloid,then the correlation between tau tangles and neuritic plaques that the authors observed does not equate to the causative sequence that the author concluded.It could well be the other way round,that as the tau tangles increases it impared mitocondria and lysosome leading to more b-amyloid.

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17. Chris on February 13, 2012 12:36 PM writes...

Does this mean that the folks at TauRx are onto something with their (supposedly) tau-dissolving Rember? And if so, what the heck is taking them so long to get to trials? (Alleged) results in summer 2008, then bupkis for three and a half years. Isn't that abnormally slow?

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18. sct on February 14, 2012 12:08 AM writes...

Chris,if you look at Taurx Website,they have been busy developing LMTX a new drug that was further improved from Rember and will be used for phase 3 trial in replacement of Rember.The patent have been granted for both EU and US.Phase 3 is very costy and the last 3 years were not the best time to raise money.The taurx website announced right issue showing that the shareholders have been funding the company directly.

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19. Gus on February 19, 2012 4:05 PM writes...

My understanding is that LMTX (a wider class of compounds, specific instances of which must be being investigated by Taurx) addresses a number of problems with the original Rember in terms of both pharmacology and patentability. Taurx have been very busy raising funds for phase III. LMTX is the only drug at this stage to target tau, so I'm keeping a close eye on this!

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20. Andrew72 on May 13, 2012 12:21 PM writes...

Someone can tell me where can j find updated information about lmtx ?

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21. ron on May 29, 2012 11:04 AM writes...

Senile plaques react for haem and are associated with small vessels, The central feature is spherical and surrounded by a shell of structures that look like caveolae. They are rosettes. Similar structures are found in the aorta at flow dividers and also in the splitting edge of atheromatous plaques. Split plaques, or spurters, are less frequent before 60 than after. Caveolins can convert APP to Abeta. Emboli cause haem deposition - microemboli can be detected post operatively by Doppler technology. Senile plaques appear to be the result of microembolism from the aorta. The age frequency fits.

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