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Three Reports on Advances in Research
Myriam
Posted: Thursday, January 26, 2012 2:25 PM
Joined: 12/6/2011
Posts: 3326


From the Alzheimer's Daily Report:

 

 

(Source: University of California, San Diego Health Sciences) - Led by researchers at the University of California (SD), scientists have created stem cell-derived in vitro models of sporadic and hereditary Alzheimer's disease, using induced pluripotent stem cells from patients with the neurodegenerative disorder. 

"Creating highly purified and functional human Alzheimer's neurons in a dish - this has never been done before," said Lawrence Goldstein, PhD, professor in the Department of Cellular and Molecular Medicine. "It's a first step. These aren't perfect models. They're proof of concept. But now we know how to make them. It requires extraordinary care and diligence, really rigorous quality controls to induce consistent behavior, but we can do it."

The feat represents a new and much-needed method for studying the causes of Alzheimer's disease. More importantly, the living cells provide an unprecedented tool for developing and testing drugs to treat the disorder.

Go to full story: http://health.ucsd.edu 

 

 

 

(Source: Temple University) - A recently discovered brain protein could play a key role in regulating the creation of amyloid beta, the major component of plaques implicated in the development of Alzheimer's disease, according to researchers at Temple University. 

A group led by Domenico Pratico, discovered the presence of the protein,12/15-Lipoxygenase, in the brain three years ago. "We found this protein to be very active in the brains of people who have Alzheimer's," said Pratico. "But three years ago, we didn't know the role it played in the development of the disease."

After two years of study, the researchers found that the protein is at the top of a pathway and controls a biochemical chain reaction that begins the development of Alzheimer's disease. Pratico said that their research has shown that 12/15-Lipoxygenase controls Beta secretase (BACE-1), an enzyme that is key to the development of amyloid plaques in Alzheimer's patients.

"For reasons we don't yet know, in some people, 12/15-Lipoxygenase starts to work too much," he said. "By working too much, it sends the wrong message to the Beta secretase, which in turn starts to produce more amyloid Beta. This initially results in cognitive impairment, memory impairment and, later, an increase of amyloid plaque."

Go to full story: http://www.newswise.com 

 

 

 

(Source: Journal of Alzheimer's Disease) - French scientists report that lack of a key brain protein was linked to Alzheimer's, a finding that threw up a tempting target for drugs to fight the disease. 

"What we've found is a weapon for controlling and modifying tau," said Etienne-Emile Baulieu of France's National Institute of Health and Medical Research, referring to a culprit involved in Alzheimer's.

Building on earlier work, researchers delved into a Paris "brain bank" of organs donated for medical science to compare levels of the protein FKBP52 in the brains of people who had died of dementia and those who had died of other causes.

In the frontal cortex, "levels of FKBP52 were 75 percent lower among people who had died of Alzheimer's and other tau diseases, a dramatic fall," Baulieu told a press conference.

Go to full story: http://news.yahoo.com 

 
 
 

Mimi S.
Posted: Thursday, January 26, 2012 3:09 PM
Joined: 11/29/2011
Posts: 7029


Thanks Myriam.


The Alzheimer's Daily News is a great place to get information, some on caregiving, but more on research. Free subscription. The articles are often also found in other major publications.


Today's issue had much to get excited about, but all need further work.


The one about a simple blood test had much too few participants to get excited about.


One of the things to look at as you read are the numbers of people involved. For example, if the total is 100 subjects, 50 each of those with the disease and 50 without. Those numbers are much too small to do more than tickle one's interest.


Also found on a different is a series of videos today from  Mayo Clinic , involving long term studies involving thousands. We won't get the answers for several years, but they will be meaningful. Thought I'd saved it for a further look, but it's gone.


If anyone comes across it, please post.


Lane Simonian
Posted: Thursday, January 26, 2012 9:22 PM
Joined: 12/12/2011
Posts: 4846


I like to look for articles on Alzheimer's disease, too, and you are doing us a great service by posting them here, Myriam.  The middle article particulary caught my attention.  The following article suggests that the disruption of zinc homeostasis (which occurs in Alzheimer's disease) is the main cause of high levels of lipoxygenases and these high levels contribute to the toxicity of peroxynitrites. http://hyper.ahajournals.org/content/20/2/138.abstract 

 

I suppose that on occasion high levels of lipoxygenase precede the loss of zinc homeostasis and in that case they could trigger the disease by increasing angiotensin II levels.  http://hyper.ahajournals.org/content/20/2/138.abstract 

Angiotensin II presents a double whammy in Alzheimer's disease: it acts through a g protein-coupled receptors (which increases phospholipase C beta activity) and it helps activate the platelet derived growth factor receptor thus activating phospholipase C gamma http://www.ncbi.nlm.nih.gov/pubmed/7759503 . http://www.ncbi.nlm.nih.gov/pubmed/19727113These two enzymes lead to the release of calcium from the endoplasmic reticulum and the activation of protein kinase C.  Protein kinase C regulates the processing of the amyloid precursor protein and this protein is cleaved by a calcium dependent enzyme http://www.ncbi.nlm.nih.gov/pmc/articles/PMC43811/ 

 

The mysterious Beta secretase (BACE-1) enzyme is nothing more than a calcium dependent enzyme (a calpain). 

 

The pathway that leads to the formation of amyloid plaques also leads to the formation of peroxynitrites.  Peroxynitrite formation is both independent and dependent upon amyloid plaque formation. 

 

To the peer advisors at the Alzheimer's Association the key points if you can sort through all this medical jargon are the following:  the pathways that leads to the development of Alzheimer's disease are known, the means to impede these pathways is also known (phenolic compounds and polyunsaturated fats), and the means to treat the disease with peroxynitrite scavengers is also known.  Cooperation from the Alzheimer's Association in utilizing this knowledge to help people with Alzheimer's disease or at risk of developing Alzheimer's disease will be greatly appreciated.


Lane Simonian
Posted: Thursday, January 26, 2012 9:32 PM
Joined: 12/12/2011
Posts: 4846


The first article mentioned in my last post is this one.  http://www.jneurosci.org/content/24/47/10616.full
JAB
Posted: Tuesday, January 31, 2012 12:16 PM
Joined: 11/30/2011
Posts: 740


Lane Simonian wrote:
I suppose that on occasion high levels of lipoxygenase precede the loss of zinc homeostasis and in that case they could trigger the disease by increasing angiotensin II levels.  http://hyper.ahajournals.org/content/20/2/138.abstract 

 

...The mysterious Beta secretase (BACE-1) enzyme is nothing more than a calcium dependent enzyme (a calpain). 

  Ummm... There's nothing "mysterious" about BACE-1 (β-site APP cleaving enzyme 1) to those familiar with Alzheimer's research.  It is one of two enzymes that are required to produce Aβ (which is neurotoxic and is also the key component of plaque) from APP.  BACE-1 is considered to be an attractive target for the treatment of Alzheimer's because it is the first step in the pathway leading to the production of Aβ, and because it has been extensively validated as a target to reduce Aβ in brain tissue using peptides and transgenic knockout models. Its expression (i.e., whether and how much of it is produced) is modulated directly by neuronal energy deficit. Studies have demonstrated that energy deprivation can cause posttranscriptional induction of BACE-1. This is an important finding because it connects neuronal energy crisis directly to amyloid hypothesis, i.e. increase in BACE-1 activity would lead to increased Aβ42 and initiate the amyloid cascade.

However, BACE-1 also has other in vivo substrates in addition to APP, including a sodium channel subunit and neuregulin 1, which modulates myelination. The function of the neurodevelopmental protein Notch is also BACE-1-dependent.  Accordingly, drugs that target this enzyme must be designed to be specific for APP cleavage, to avoid significant side effects. 

See, e.g.:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3226269/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879045/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2907124/
http://www.biomedcentral.com/content/pdf/cd-972717.pdf

(Interestingly, none of these papers, and none of the many dozens of papers that cite them, ever mention peroxynitrite.  I wonder why that is.)

Targeting 12/15-lipoxygenase instead of directly targeting BACE-1 might give a treatment route that might avoid those side effects. Note that other upstream enzymes have been tentatively identified as targets that could also be used to modulate BACE-1 activity, e.g., cellular S1P:
http://www.neuro.cjb.net/content/31/18/6850.full

(Alternatively, if one could modulate cellular energy and indirectly lower BACE-1 activity, that could accomplish dual objectives of safety and efficacy.  That might be one of the mechanisms of action involved in ketone body therapies such as Axona.)



JAB
Posted: Tuesday, January 31, 2012 12:23 PM
Joined: 11/30/2011
Posts: 740


Lane Simonian wrote:
To the peer advisors at the Alzheimer's Association the key points if you can sort through all this medical jargon are the following:  the pathways that leads to the development of Alzheimer's disease are known, the means to impede these pathways is also known (phenolic compounds and polyunsaturated fats), and the means to treat the disease with peroxynitrite scavengers is also known.  Cooperation from the Alzheimer's Association in utilizing this knowledge to help people with Alzheimer's disease or at risk of developing Alzheimer's disease will be greatly appreciated.

  Mimi is a Peer Volunteer, not a "peer advisor".  She has Alzheimer's disease herself, and is a source of inspiration to the rest of us since she adheres to Best Practices and has had remarkably good results from it.
 

Peer Volunteers are members just like the rest of us, and either are caregivers for a loved one with dementia or have dementia themselves.  They help make the message boards a better place to be, by welcoming newcomers, making sure that people feel comfortable here, detecting and heading off negative interactions, etc.

 

They do not "advise" the Association.

No one from the Alzheimer's Association reads this forum.  And the Alzheimer's Association staff most certainly do not look here for information or advice.

So if you've been hoping to influence the Association's priorities for funding or lobbying by peppering this forum with references to peroxynitrite, you'll have to find a different route.


Lane Simonian
Posted: Tuesday, January 31, 2012 3:44 PM
Joined: 12/12/2011
Posts: 4846


The peer volunteers often do give advice (which is much appreciated).  I don't know who reads this website.  My main goal when I write for this or any other site is to explain the disease as clearly as I can and discuss possible ways to treat it so that people can help their loved ones.  If during that process, I make contact with someone who can help me with my research (as has happened) or can help disseminate this information to a larger audience  I am very grateful. 

 

I have had an aunt and a cousin die from Alzheimer's disease and a mother who has had Alzheimer's disease for eight years.  I have spent eight years and hundreds of hours researching this disease.  I don't mind people disagreeing with me, as long as they are respectful and present reasonable counterarguments.

 

I say the BACE-1 enzyme is mysterious in that few people have corectly identified what activates it.  The following researchers are one of the only ones to do so.  They note that protein kinase C processes the amyloid precursor protein and that a calcium independent enzyme cleaves it http://www.ncbi.nlm.nih.gov/pmc/articles/PMC43811/ 

Both are activated by phospholipase C.  Peroxynitrites are not mentioned because they do not activate phospholipase C; they are the result of phospholipase C activation (just as amyloid plaques are).  Phenolic compounds (in various fruits, vegetables, spices, and essential oils) and polyunsaturated fats (such as fish oil--an Omega 3-fatty acid) inhibit phospholipase C y (gamma) and thus may contribute to the protection against Alzheimer's disease.

http://www.sciencedirect.com/science/article/pii/S0005276098000447 

http://bloodjournal.hematologylibrary.org/content/101/9/3534.full 

http://www.ncbi.nlm.nih.gov/pubmed/16266772 

 

Lipoxygenases do regulate Angiotensin II levels but this is only one of many risks factors for Alzheimer's disease, so its inhibition probably does not help most people early in the disease. 

 

You know a lot about this disease, JAB, but please try to keep an open mind and try to be polite. There is no reason to be contemptuous and dismissive.

 

 


JAB
Posted: Tuesday, January 31, 2012 6:00 PM
Joined: 11/30/2011
Posts: 740


What I am is very frustrated by your repeatedly presenting highly speculative hypotheses as if they were known fact, and then repeatedly ignoring clearly-stated requests to provide links to the supportive evidence in the scientific literature.

 

I am also very frustrated by the fact that every time I try to pin down where one of your more ... ah ... startling statements is coming from, you persist in flooding your supposed reply with all sorts of totally irrelevant subjects and references to unrelated papers, if not completely changing the subject.

 

I would appreciate it if:

 

 (a) You would stop making sweeping generalizations such as "the pathways that leads to the development of Alzheimer's disease are known", "the means to impede these pathways is also known (phenolic compounds and polyunsaturated fats)", and "the means to treat the disease with peroxynitrite scavengers is also known".  None of those is true.  See, for example, the exhaustive 727-page study conducted for the National Institutes of Health by a panel of world-renowned experts on purported risk factors and purported protective factors:

http://www.ncbi.nlm.nih.gov/books/NBK47456/
and the Cochrane database reviews on aromatherapy for treating Alzheimer's (aromatherapy being, as far as I could tell from the last time you made this type of statement, your basis for claiming that peroxynitrite scavengers are "known" to treat AD.)

 

(b) You would clearly differentiate between the hypotheses that you have developed, and the hypotheses that are reasonably broadly accepted by the experts in the scientific community who are studying Alzheimer's.

 

(c) You would stick to reputable sources for your supportive evidence, e.g., papers published in top-tier peer-reviewed journals, rather than blogs written by people who have questionable qualifications, or ads from sites that sell nutritional supplements.

 

Once again, I would note that the Alzheimer's Association changed the name of this forum to remind us, every time we come here, that preclinical data is unreliable at best, and quite possibly totally irrelevant, unless and until it has been verified by well-designed and -powered clinical trials.

 

The Alzheimer's Association has a very clear policy of supporting only those treatments which have made it successfully through multiple Phase III clinical trials and are FDA-approved.

 

The Association refuses to endorse even prescription-only medical foods that are widely prescribed by doctors for Alzheimer's patients and have substantial clinical evidence behind their use.


Lane Simonian
Posted: Tuesday, January 31, 2012 8:04 PM
Joined: 12/12/2011
Posts: 4846


What I object to you is that you find fault with all the scientific studies that I cite.  Let's try some of the major ones again.

http://www.jneurosci.org/content/17/8/2653 

http://www.ncbi.nlm.nih.gov/pubmed/16816118 

http://www.ncbi.nlm.nih.gov/pubmed/19356025 

http://www.jbc.org/content/266/7/4244.abstract 

http://cogprints.org/4095/ 

 

So let's go down the line (and remember this is not me saying it, it is respected scientists in the field).

 

Peroxynitrite-mediated damage is widespread in Alzheimer's disease.

Peroxynitrites can contribute to the hyperphosphorylation and nitration of tau proteins.

Peroxynitrites lower intracellular levels of magnesium resulting in the influx of calcium and efflux of glutamate killing neurons.

Peroxynitrites oxidize sulfhydryl groups including cysteine that are needed to activate g protein-coupled receptors (such as those involved in memory, smell, mood, sleep, social recognition and alertness).

 

Even though you dislike them, you can read on another post all the animal studies for Alzheimer's disease in which peroxynitrite scavengers have ameliorated cognitive decline.

 

Even though you don't like the clinical trials, small-scale clinical trials indicate that essential oils reversed cognitive decline in every patient with Alzheimer's disease.

 

Sure, I would like to have phase III clinical trials.  The Alzheimer's Association hides behind that demand.  But every single alternative treatment for Alzheimer's disease posted on their alternative treatment website has not been through a phase III clinical trial and yet that it what they want for aromatherapy. 

 

For many years the scientific community has focused on amyloid plaques and the hyperphosphorylation of tau proteins.  It is as if they are permanently stuck in quicksand.  A few scientists have tried to elucidate the pathway and processes that lead to these two supposed hallmarks of the disease: amyloid plaques and hyperphosphorylated tau proteins.

 

Li and his colleagues outlined the possible role of peroxynitrites in the hyperphosphorylation and nitration of tau proteins.  18 years ago, Buxbaum and his colleagues found the pathway that leads to the formation of amyloid plaques

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC43811/.  If people had accepted the findings made by a series of respected scientists and used those findings to construct a solid hypothesis and tested that hypothesis, we would likely be much closer to providing an effective treatment for Alzheimer disease today.

 

Recently peroxynitrites were identify as a potential reason why amyloid plaques are so hard to get rid of.

http://www.cell.com/neuron/abstract/S0896-6273(11)00595-2 

 

So if all the risk factors for Alzheimer's disease contribute to the formation of peroxynitrites (high glucose levels, high blood pressure, chronic bacterial and viral infections, the APOE4 gene, presenilin gene mutations, bisphosphonate osteoporosis drugs, late estrogen replacment therapy, aluminum fluoride, sodium fluoride, mercury and stress for instance), if all the preventive measures inhibit the formation of peroxynitrites (phenolic compounds and polyunsaturated fats, for instance), if the pathways that lead to the formation of amyloid plaques (phospholipase C gamma and beta) also lead to the formation of peroxynitrites, if peroxynitrite damage is widespread in Alzheimer's disease, and if peroxynitrite scavengers have ameliorated cognitive decline in animal models, case studies, and clinical trials of Alzheimer's disease what other conclusion do you wish me to make?