a special program of the National Emergency Medicine Association (NEMA)

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Week: 584.7 

Guest: Dr. John Trojanowski, Dir. Alzheimer's Ctr, Univ. of Pennsylvania 

Topic: New Alzheimer's brain plaque  

Host/Producer: Steve Girard 

NEMA: Alzheimer's disease has been a great cause for distress as we get older, individually and as a society. Spurred by that concern, there's been an enormous amount of research into the brain numbing condition. We have Dr. John Trojanowski, head of the Alzheimer's Center at the University of Pennsylvania with us today...whose research team has made a new discovery that could lead to further defining and solving the problems of Alzheimer's. Dr. Trojanowski, can we first talk about the history behind other discoveries in Alzheimer's Disease?

TROJANOWSKI: Alzheimer's disease has undoubtedly been an affliction that has affected mankind since the first human reached 60 years of age. It wasn't recognized as a specific disease tendency until this century. And so, what happened in 1907 is that Dr. Alzheimer put together plaques and tangles with a progressive dementia, and forever after referred to as Alzheimer's disease. We assumed for many, many years that it was a fairly unitary entity, but we now recognize as multiple variations on the disease, and also multiple causes for the disease. And we now know that there are sporadic forms of the disease, that is, about 90% of cases are sporadic... having no single gene as the basis or cause of the disease, but 10% of Alzheimer's patients develop a familial or hereditary form of the disease. And of the 100 or so families that have been well characterized...half of them have their disease assigned to mutations in one of three genes on one of the three different chromosomes. All of these genes and the mutations are the product of research that has taken place over the last ten years. There's really been a tremendous upsurge in new discoveries.  

NEMA: What is the substance called Amyloid...that we've found deposited in the brains of Alzheimer's victims?  

TROJANOWSKI: I mentioned the tangles and the plaques as the brain hallmarks of the disease...if you don't have plaques and tangles, you don't have Alzheimer's disease...even though I've already said there's multiple, different cause...that is these that we can, I think, talk about as a readily identifiable entity, based on the finding of dementia that's progressive in an older person...and then at death, the abundance of plaques and tangles. The tangles are inside nerve cells, formed by a protein called TAU, which assembles into masses of filaments. And outside of nerve cells, in fact, outside of all the cells in the brain...so it's in the brain but not within a cell, are the amyloid deposits. So, the tangles are filaments, but they're inside of cells, and the amyloid also is a filament pathology, but that's outside of cells. The building blocks of those filaments, that is, the proteins that make them up, are fragments of a larger protein...and those fragments are called "A beta", "Beta amyloid peptides". And this is all the new stuff that I'm referring to that has been deciphered in the last ten or fifteen years, including the sequencing and cloning of the TAU genes, and the "A beta" precursor protein genes...and the discovery of mutations in the amyloid precursor protein genes. Which in less than one percent of all familial Alzheimer's disease is the cause of the disease. So, it's a rare cause of the disease, when you have a mutation, but it is instructive to understand the effect of those mutations, because understanding may provide ways to treat the more common, sporadic, non-hereditary forms of the disease.  

NEMA: Since the amyloid deposit is a sort of waxy protein, what is the current thought on why so much is produced that it interferes with brain function?  

TROJANOWSKI: You mentioned overproduction, and in the genetically determined forms of the disease, that may be the explanation. That there is not an increase in the precursor protein, the parent protein, but an increase in the metabolic pathway...leading to the production of A beta. So it's how a protein gets diced up, cleaved, chopped...into small parts so it can be eliminated...but in patients with the mutation, there is much, much more of this small peptide - the A beta peptide - that are produced. So, it's appealing to think that the mutations, both in the amyloid precursor protein and in these other two genes that we haven't talked about, causes disease by the over production of the A beta peptide. In sporadic Alzheimer's, is may well be a failure to clear...so, if you and I are producing this peptide, and we clear it as we make it, we may live to be 90, 100, 110...never develop plaques, or Alzheimer's disease because our clearance mechanisms match our production of the A beta peptide. Not unlike...there's analogies to more familiar disorders... we make new blood cells all the time, and if too many are made, we're talking leukemia. Or if too many are made and they're not eliminated in a way that matches the production, we're talking leukemia. So in an analogous way, if there's too much of this A beta peptide made, it could be a problem...if it's cleared too slowly, there could be problems. 

NEMA: Your new research uncovered a new substance, also present in the brain...is it related to the amyloid deposits, and how might it play a role in Alzheimer's...?  

TROJANOWSKI: It's not amyloid, and that was the very striking observation that I think has caught the imagination of the scientific community. It's a plaque...the accumulation of stuff that shouldn't be in there. Waxy deposits are a good way to think of it... "gumming up the brain"...so, these new plaques that we've described don't have the properties of amyloid, and these deposits, we discovered, it was possible to visualize and demonstrate with antibodies, to a new protein that has never been recognized as forming deposits before - it may indeed be a known protein that has been cloned and sequenced by others, but for the first time has been found to cause a plaque, based on our data. It's completely separate from amyloid plaques, occupies as much volume as a plaque...so we would assume it would be just as deleterious, or problematic for brain function as amyloid, and it appears to be as specific, or perhaps even more specific to Alzheimer's disease than amyloid, since some normal elderly individuals over 55 or 60 can have some amyloid deposits and not be demented.    

NEMA: These deposits ...do they engulf, or swallow brain matter, or just surround it...?  

TROJANOWSKI: I guess it would be similar to pouring honey or some other sticky fluid onto a computer processing unit. Stuff sort of seeping in and lifting off the connections or the contacts between chips and so forth...interfering with the signaling in the CPU. This is what we assume amyloid does...and by analogy, the new plaque lesion that we described probably does something similar.  

NEMA: In many of the stories we do on genetic research, I hear, "we're hoping to find or establish a marker...a way to identify that something is happening, before it gets to a more serious stage".  

TROJANOWSKI: We are trying to purify the protein at this very minute, and if we have the letter sequences, the amino acid sequence of the protein, we'll know what it is...so we need to conduct an exercise much like a crossword puzzle, fill in the letter codes of this protein, and then be in a position to do a number of things. Devise tests based on the identity of the protein and its changing levels in the disease... one can make cell culture models by introducing the gene into cultured cells...animal models by introducing the gene into small animal models. All of these things would enable one to understand the meaning of these plaques for brain function. Also, enable efforts to develop diagnostics...and most importantly, of course, new therapies.  

NEMA: There's been so much news in genetic research...specifically in brain disease...don't want to jinx it by calling them breakthroughs...  

TROJANOWSKI: I think it's fair to call them breakthroughs. They...science builds a story incrementally, and sometimes you take great leaps forward in deciphering a story of how this or that or the other disease develops, and I think We're taking big leaps forward at a fairly rapid rate in the last decade...to a scientist...they look like breakthroughs.  

NEMA: Dr. John Trojanowski, director of the Alzheimer's Center at the University of Pennsylvania. He says that it's a very exciting time to be doing this research, and though someone in the end stages of Alzheimer's may see little benefit from today's breakthroughs, but that we should all take heart in knowing the tremendous progress being made in genetic, vitamin and hormonal studies surrounding the disease.  

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NEMA: Thanks for joining us for today's program. If you have any comments or suggestions, contact this station. Or visit our home page at: www.nemahealth.org/  

...for a look at transcripts of this or past programs, or to find out more about the National Emergency Medicine Association. I'm Steve Girard at The Heart of the Matter.