Replies to post #133183 on Biotech Values

[genisi]

IMHO and FYI this is the most relevant publication for Alzheimer's

Bear in mind that the Genentech group work was done in developing peripheral embryonic mouse neurons, deprived of growth factor. At this point relevance of APP–DR6 to adult CNS tissue and to AD specifically, remains to be shown.

What I find compelling is that the mechanism, activation of death receptor 6, brings together all the known pieces of Alzheimer's pathology

There are many compelling observations to support their hypothesis and it does connect APP, BACE, and Swedish mutation, but has a few holes as well. Two missing pieces are how do p-Tau in the tangles and Aß in the plaques fit in the mechanism. This mechanism also cannot explain AD caused by other mutations in the presenilin genes or in the Aß site of APP. Btw, I don't believe any single mechanism will bring together all the pieces of AD.

a search of the patent filings indicates that they are still actively pursuing this target.

I would too :-) No doubt this is just the begging.

[Kadaicher1]

Jellybean, I thought the APP signal to the DR6 was to cull a cell that was malfunctioning and dying. Trophic factor(food) deprivation preceeds the DR6 signal. That is neural pruning. That is perhaps not how most cells die in Alzheimer's. Thats not to say that excessive pruning couldn't trigger excitotoxicity. But how is cutting off the Bace going to stop the trophic-factor deprivation. Am I missing something here? Just from what I have read in that abstract it looks like maybe chopping into the process to cleave the APP may even have an adverse effect.
http://www.sciencedaily.com/articles/e/excitotoxicity.htm
Excitoxicity is seen as a cause of neuron death over various neurodegenerative diseases.
http://www.alscenter.org/living_with_als/causes/excitotoxicity.html
Blocking the glutumate receptors was seen as a way to stop excitotoxicity. Strong argonists of the NMDA glutamate receptors proved to have severe side effects, but a weak argonist was tolerated and LLY developed Memantine in '68 and it is still in use in many forms.
http://en.wikipedia.org/wiki/Memantine
A recent trial in Huntington's, which is another neurodegenerative disease where excitotoxicity is thought to be the final damage, Memanine caused some cognition gains, but increased movement disorder.
http://hddrugworks.org/index.php?option=com_content&task=view&id=141&Itemid=88
Prana's PBT2 will be the next drug to go against Huntingtons with a 6 month trial due to start shortly. A totally different MOA to anything so far and thought to protect against exitotoxicity through its interaction with intracellular metals.
Assoc Professor Kevin Barnham at the Mental Health Research Institute(Melbourne) was recently awarded $419,000 to further research PBT2's effect on excitotoxicity.
http://www.pranabio.com/downloads/Media%20Releases/Media%20Releases%202011/Oct%2027%20Aust%20Fed%20Gov%20Grant%20to%20study%20role%20of%20PBT2%20in%20preventing%20ecitotoxicity.pdf

In saying all the above there is another aspect.
[ In late 2010, for example, a team led by Mathias Jucker at the University of Tübingen, Germany, reported that they could, in essence, transmit Alzheimer's-type brain pathology in a prion-like manner by injecting Alzheimer's brain matter into the bodies of mice (Eisele, Y. S. et al. Science 330, 980–982, 2010). Such findings have contributed to a major rethink of the cause of Alzheimer's disease]

It is contageous just as is mad cow disease.

That was the same experiment Stanley Prusiner performed when defending his Prion work in the 90s.
http://www.slate.com/articles/news_and_politics/hey_wait_a_minute/1997/10/nobel_gas.html

A prion is just a little fragment of protein that can reproduce. Maybe like that little protein fragment that hits the DR6.

Exitotoxicity is assosciated with various conditions, including traumatic brain injury and stroke. Kevin Barnham's work may prove to be very important.

[DewDiligence]

Roche’s crenezumab is first AD drug to be tested on humans with no signs of dementia:

http://in.reuters.com/article/2012/05/15/us-alzheimers-genentech-idINBRE84E0UJ20120515

The drug will be tested among members of an extended family of about 5,000 people from the Antioquia region of Colombia. They carry a gene that causes them to develop Alzheimer's early, with some experiencing symptoms of memory loss in their mid-30s, scientists say.

The U.S. Department of Health & Human Services is backing the trial with a $16 million grant as part of the government's National Alzheimer's Plan announced on Tuesday… Another $15 million in trial funding comes from Banner Health, a non-profit organization based in Phoenix, Arizona, that runs a chain of hospitals and which is leading the study. The rest of an estimated $100 million in total costs will be paid by [Roche]…