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Print ArticleIn an important advance in the battle against Alzheimer's disease, physician-scientists at NewYork-Presbyterian Hospital/Weill Cornell Medical Center have identified naturally occurring antibodies in human blood that may help to defend against this form of dementia as well as other neurodegenerative diseases.
The newly found antibodies selectively target aggregates of beta amyloid proteins called "oligomers" that are toxic to brain cells, while ignoring the benign single-molecule forms of the same proteins. The existence of such antibodies was predicted by animal studies, but they were never previously demonstrated to be present in substantial quantities in blood from normal humans.
Lead researcher Dr. Norman Relkin, a behavioral neurologist and neuroscientist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, will present the findings on Monday, June 11, at 3:30 pm, at the "2nd Alzheimer's Association International Conference on Prevention of Dementia," in Washington, DC.
Dr. Relkin is director of the Memory Disorders Program at NewYork-Presbyterian/Weill Cornell and associate professor of clinical neurology at Weill Cornell Medical College.
Dr. Relkin's team has been testing an antibody-based immunotherapy called Intravenous Immunoglobulin (IVIG) as a potential new treatment for Alzheimer's. IVIG is made from the blood of healthy donors and was previously reported to contain small quantities of antibodies against beta amyloid.
"The effects of IVIG in lowering beta amyloid levels in Alzheimer's patients in our Phase I clinical trial were much more profound than we expected," Dr. Relkin explains. "We couldn't readily explain this based on the low levels of anti-amyloid antibodies known to be present in IVIG. We suspected there might be another, unseen player."
His laboratory studies demonstrated that IVIG initially bound very little single-molecule ("monomer") beta amyloid in a test tube. However, it gathered up much more of the protein when the amyloid was "aged" in a way that allowed soluble aggregates to form.
These beta amyloid "oligomers" can grow into insoluble "fibrils" that cluster around brain cells and are a hallmark of Alzheimer's disease. While monomers are produced from birth and appear to be relatively benign, oligomers have been implicated as potent toxins responsible for Alzheimer's-linked memory loss and brain cell death. This has led many scientists to speculate that oligomers may be the main culprit in Alzheimer's and therefore a prime target for a new generation of disease-modifying treatments.
To further confirm that these natural antibodies bind with oligomers, Dr. Relkin and his colleagues collaborated with Drs. Charles Glabe and Rakez Kayed from the University of California at Irvine, who had previously created anti-oligomer antibodies in rabbits. Using techniques pioneered by Dr. Glabe's group, the NewYork-Presbyterian/Weill Cornell scientists were able to measure and extract the human version of anti-oligomer antibodies from IVIG and then demonstrate that these antibodies are present in the blood of normal individuals.
The basis for the selective recognition of oligomers by these antibodies appears to be their capacity to recognize the oligomer's misfolded shape.
"That was a surprise, because most antibodies work by recognizing some aspect of the chemical structure of their target -- not their shape," explains Weill Cornell Medical College molecular biologist and study co-author, Dr. Paul Szabo. "That means that even though beta amyloid monomers and oligomers have the same fundamental chemical makeup, human anti-oligomer antibodies can distinguish between them. The antibodies recognize a particular shape that proteins assume only when they become these toxic aggregates."
The ability of the antibodies to recognize toxic proteins based on their shape may have important implications for immune therapy of other neurologic disorders, the researchers explain.
"We were able to confirm that the antibodies we found not only recognize oligomers of beta amyloid but also unhealthy forms of other proteins that accumulate in a wide variety of diseases, such as Parkinson's, Lewy body dementia and Prion disease (the human form of ‘Mad Cow' disease), to name a few," says Dr. Relkin.
Since beta amyloid oligomers are much less abundant in the body than the single-molecule variety, the relatively high amount of oligomer-specific antibody found in human blood suggests that the immune system recognizes these aggregates to be a particularly noxious threat.
"This could be part of an innate defense mechanism against Alzheimer's and other age-related neurodegenerative disorders," comments Dr. Marc Weksler, The Irving Wright Sherwood Professor of Geriatrics and professor of medicine at Weill Cornell Medical College, and senior investigator in the Phase I IVIG study that led to this discovery.
However, the clear demonstration of the relationship of these scientific findings to clinical benefit in patients requires much more study, the experts say.
NewYork-Presbyterian/Weill Cornell is currently leading a six-month Phase II study of IVIG in 24 patients with mild and moderate Alzheimer's disease, which is planned to be complete later this year. While this study may provide a signal of the effect of IVIG therapy to clinical outcomes, further investigation in larger controlled and longer-term trials will be needed to definitively demonstrate whether IVIG is useful in treating Alzheimer's.
Still, this discovery substantially boosts our understanding of Alzheimer's and other neurodegenerative illnesses, the experts say. Source : New York- Presbyterian Hospital/Columbia University Medical Center
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I read with the interest article "Newly discovered antibody may be body´s natural defense against Alzheimer´s", so I think, there is another proof about prion diseases "non- infectiosity". Also other new findings (February 2007), offer significant insights into normal folding mechanisms as well as those that lead to abnormal amyloid fibril conversion ( http://www.sciencedaily.com/releases/2007/02/070212182836.htm). Until about five or six years ago, everyone assumed that the large amyloid plaques, or neurofibrillary tangles, that were found in the brains of Alzheimer 's victims were the cause of the disease. However, recent scientific discoveries indicate that these large, insoluble aggregates might merely be markers of the disease—they do not cause the disease ( http://www.sciencedaily.com/releases/2007/02/070215110558.htm).
An international team of chemists and molecular biologists reported (April 2007); „A mystery on which the new Nature paper sheds light is what causes different strains of prions (infectious proteins) in which the protein sequence is identical. Our research gives a strong hypothesis that the origin of prion strains is encoded in the packing of the molecules in the fibrils which we are seeing in the crystals…". They found that; Alzheimer's disease, Parkinson's disease, type II diabetes, the human version of mad cow disease and other degenerative diseases are more closely related at the molecular level. (http://www.sciencedaily.com/releases/2007/04/070430102021.htm).
In addition, see also my "opinion- articles"; about the link between BSE and Alzheimer´s disease ( http://www.medicalnewstoday.com/youropinions.php?opinionid=11677 ) and the link between the hyperfunction (neurodegenerative diseases; Alzheimer´s disease…) and the hypofunction of glutamatergic (NMDA receptor) neurons in schizophrenia (http://www.medicalnewstoday.com/youropinions.php?opinionid=17968 ).
I described an alternative "BSE ammonia-magnesium" theory ( http://www.agriworld.nl/feedmix/headlines.asp?issue=3). This theory is based on the chronic Mg-deficiency- potentiated by hyperammonemia (high protein intake…). These mechanisms have a strong influence on CNS, especially in ruminants and carnivora animals ( www.bse-expert.cz). Also according to the recent research; BSE can be "not infectious disease ". Why? At first, authors in „Journal of Pathology" (March, 2006) found that prion proteins implicated in the development of transmissible spongiform encephalopathies, such as vCJD, may be markers for disease rather than the infectious agents. So, under laboratory circumstances prion-protein can be absorbed across the gut, it also shows that this is unlikely to occur in real life ( http://www3.interscience.wiley.com/cgi-bin/abstract/112568745/ABSTRACT ).
And what is about the possibility of sporadic mutations- transmission of the disease gene? There is the explanation from Dr.Murphy (President of the International Committee on the Taxonomy of Viruses), he says;
„Recent research has shown that the scrapie PrP protein differs from the BSE PrP protein at only seven amino acid loci, whereas the BSE PrP protein differs from the human CJD PrP at more than 30 loci. These differences explain the concept of strains and help explain why prions from one species might jump more easily into another species than another. It is difficult to find the terms to discuss prions — for example, can we talk about mutants when there is no DNA? What would Watson and Crick think of all this? There is a familial form of CJD, accounting for about 10% of cases. In the familial disease there is are mutations in the gene encoding the normal protein such that the protein tends to fold in the abnormal way and tends to pile up into aggregates in brain cells with lethal consequences ….. The prion protein in familial cases is the same in each family member that has it, and different in all other families. Sometimes the difference is as small as one amino acid, but these differences can be used to determine the pedigree of the prion. I 'm sure such analyses are being applied to the 10 cases just reported in the UK" ( http://www.accessexcellence.org/WN/NM/madcow96.html).
Other authors in „Journal Biol. Chem." (November, 2006) found that small amounts of detergent-insoluble PrP aggregates are present in uninfected human brains, so insoluble aggregates and protease-resistant conformers of prion protein in uninfected human brains ( http://www.jbc.org/cgi/content/abstract/281/46/34848). More recently (February, 2007) authors in "Neuron" wrote; "Early functional impairments precede neuronal loss in prion disease…they occur before extensive PrPSc deposits accumulate …supporting the concept that they are caused by a transient neurotoxic species, distinct from aggregated PrPSc" . ( http://www.neuron.org/content/article/abstract?uid=PIIS0896627307000086).
The prion protein infection from transmissible BSE is then thought to travel to the brain via peripheral nerves, perhaps with assistance from the lymphoreticular system. In 2004, a study of 13,000 appendix and tonsil samples revealed that thousands of people may be unknowingly harbouring vCJD ( http://news.bbc.co.uk/2/hi/health/6334215.stm). However, recently scientists find connection between nerve cells and immune system. They have made visible an astounding number of contacts between immune and nerve cells. These include some of the most important immune cell types, such as B-lymphocytes, T-lymphocytes and dendric cells - all of which form connections to the nerves ( http://www.news-medical.net/?id=21792).
Also, according to the article „Should we still be worried?" (January 10, 2007) ( http://www.guardian.co.uk/g2/story/0,,1986657,00.html), there is an agreement about the „BSE no infectiosity" – see following text from this article; „ But despite billions spent on efforts to save Britain's beef industry and protect its citizens, all the major questions remain unanswered. The origin of the disease? A mystery. The number of people infected with vCJD? A mystery. The risk that those harbouring the disease will infect others? Again, a mystery …. The politicians didn't know what to do and the scientists didn't know what to do. We didn't know where it came from, what caused it, how bad it might be. We didn 't know anything…. „The danger now is not from cattle, it's from other human beings," says another expert in vCJD …".
This can be in connection that the story of BSE in Britain is a consequence of „intensive farming" (metabolic disease disease and „neurotoxicity") and belongs in the „Organic Research" ( http://organicresearcher.wordpress.com/2007/01/06/bse-an-alternative-theory/). My alternative "BSE ecological view" can be well documented concerning the example "Chronic Wasting Disease" (CWD) http://organicresearcher.wordpress.com/bse-the-work-of-josef-hlasny/. Also recent experiments on mice indicated that mad cow disease in cattle was not contagious (May, 2007). The research group, headed by Tetsutaro Sata, chief of the Department of Pathology at the National Institute of Infectious Diseases (Japan), is now compiling a detailed academic paper based on the findings. So, if the infection cannot be confirmed through the experiments between mice, then it would be difficult to verify the infectiousness (of BSE) http://www.asahi.com/english/Herald-asahi/TKY200705100081.html ). So, where is a central role of infectious proteins (from meat and bone meal- „MBM") in BSE? For example; why we found BSE positive animals – three or more years after a ban on using MBM in dairy rations? (see examples from Europe, Canada, Japan)? So, there is the evidence that MBM is not „an origin about the BSE ", beef is safe in the all world…
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